Unit doses, aerosols, kits, and methods for treating heart conditions by pulmonary administration

ABSTRACT

Methods of treating atrial arrhythmia include administering an effective amount of at least one antiarrhythmic pharmaceutical agent to a patient in need thereof, such that the at least one antiarrhythmic pharmaceutical agent first enters the heart through the pulmonary vein to the left atrium. Other methods of treating atrial arrhythmia include administering by inhalation an effective amount of at least one antiarrhythmic pharmaceutical agent to a patient in need thereof. An amount of the at least one antiarrhythmic pharmaceutical agent may peak in the coronary sinus of the heart at a time ranging from 10 seconds to 30 minutes from initiation of the administering. Unit doses, aerosols, and kits are also contemplated.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to compositions, unit doses, aerosols, andkits for treating certain heart conditions by pulmonary administrationand methods thereof.

2. Background Art

Cardiac arrhythmia (also dysrhythmia) is a term for any of a large andheterogeneous group of conditions in which there is abnormal electricalactivity in the heart. The heart beat may be too fast or too slow, andmay be regular or irregular.

Atrial arrhythmia is a field with a high level of unmet clinical need.Many drugs used today have been on the market since the early 1980s and1990s and are mostly inadequate due to either lack of efficacy or aside-effect profile that is primarily cardiac related, that necessitatesextensive monitoring of the patient.

What is needed for fast and safe cardioversion (resolution ofarrhythmia) is therapy that:

1. Has little to no risk of acceleration of ventricular rate beforecardioversion;

2. Slows atrio-ventribular (AV) conduction so that there is rate controland cardioversion at the same time;

3. Has little to no effect in prolonging the QRS interval and shouldhave a low risk of torsade de pointes; and

4. Has little to no negative inotropic effect; it should have only mildnegative chronotropic effect, without the risk of severe bradycardiawhen the patient reverts to sinus rhythm.

None of the current approved drug products exhibit thesecharacteristics. High oral and intravenous (IV) doses required tocompensate for absorption, metabolism, and dilution result in blood highblood concentrations for an extended period of time that cause thedangerous adverse cardiac events like pro-arrhythmias, QT prolongation,and torsade de pointes. FELDMAN et al., “Analysis of Coronary Responseto Various Doses of Intracoronary Nitroglycerin,” Circulation,66:321-327 (1982); and BARBATO et al., “Adrenergic Receptors in HumanAtherosclerotic Coronary Arteries,” Circulation, 111:288-294 (2005).Comorbid conditions also limit use of ideal drugs in some patients, forexample the case with intravenous adenosine. GAGLIONE et al., “Is ThereCoronary Vasoconstriction after Intracoronary Beta-adrenergic Blockadein Patients with Coronary Artery Disease,” J Am Coll Cardiol, 10:299-310(1987). Drugs like verapamil and diltiazem injections are second line oftherapy requiring close monitoring of patients. NOGUCHI et al., “Effectsof Intracoronary Propranolol on Coronary Blood Flow and RegionalMyocardial Function in Dogs,” Eur J Pharmacol., 144(2):201-10 (1987);and ZALEWSKI et al., “Myocardial Protection during Transient CoronaryArtery Occlusion in Man: Beneficial Effects of Regional Beta-adrenergicBlockade,” Circulation, 73:734-73 (1986).

Paroxysmal atrial fibrillation (PAF) is a subset of the overall atrialfibrillation (AF) population and is estimated to be 25-30% of theoverall AF population. About 2.5 million patients are affected by AF inthe United States. The population of PAF patients is estimated to be900,000 to 1.5 million worldwide.

Paroxysmal supraventricular tachycardia (PSVT) is an arrhythmia thataffects younger and healthy populations who are active (e.g., athletes).About 500,000 to 600,000 patients have PSVT in the United States.

Ablation techniques, e.g., RF ablation, are often used to treatarrhythmias. But ablation is expensive with the cost typically rangingfrom about $25,000 to $36,000 per procedure. Despite the high expense,ablation may not completely correct the arrhythmia. Often, multipleablation procedures are required to achieve a satisfactory result.

Oral medications, e.g., pills, tend to require high doses and time foronset of action. The oral dose for heart medications generally tends tobe well over 1 mg. High doses increase the likelihood of side effectsand drug-drug interactions as these patients typically take multiplemedications. The time for onset for oral cardiovascular medicationstends to be around 60 minutes. Oral antiarrhythmic medications have beenpredominantly developed for prevention with treatment being givenintravenously.

Intravenous injection usually requires a hospital environment foradministering a medicine and typically involves a visit to the emergencyroom (ER). These overheads result in this therapy being expensivecompared to therapies where the patients can self-administer theirmedicines. Intravenous injection requires a dose that is higher thanwhat is actually needed in the heart to compensate for dilution andmetabolism. Drug injected by IV passes through the right side of theheart and then the lungs before reaching the left side of the heart. SeeFIG. 1. The drug remains in the blood stream at a high concentrationbathing all the organs and tissues with this drug in a highconcentration, until the drug gets excreted through the kidneys orthrough other metabolic routes (e.g., hepatic). As a result, IV drugsmay cause unwanted side effects. Drugs administered via the IV route aresignificantly diluted in the venous blood volume and lungs beforereaching the cardiac circulation.

Injecting the heart directly is usually a last-resort taken by acardiologist as a life saving measure in an emergency. The doses of thedrugs injected directly into the heart in this manner are usually lessthan their IV and/or oral doses.

In some cases, an unplanned surgery is necessary to save the patient'slife. Of course, unplanned surgeries are expensive and risky to thepatient.

Cardiac arrhythmias are associated with disabling symptoms liketightness around the chest, palpitations, feeling tired, and sometimeschest pain.

In view of the above, arrhythmias frequently result in emergency room(ER) visits, where intravenous drugs are administered, sometimesnecessitating an extended stay in the hospital and in some cases alsoleading to unplanned invasive procedures. Pipeline Insights:Antiarrhythmics, Datamonitor (06/2006); and TWISS et al., “Efficacy ofCalcium Channel Blockers as Maintenance Therapy for Asthma,” British Jof Clinical Pharmacology (November 2001).

There remains, however, a need for improved compositions and methods fortreating heart conditions. Accordingly, there also remains a need formethods of making these compositions.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides compositions, unit doses,aerosols, kits, and methods for treating certain heart conditions. Otherfeatures and advantages of the present invention will be set forth inthe description of invention that follows, and in part will be apparentfrom the description or may be learned by practice of the invention. Theinvention will be realized and attained by the compositions and methodsparticularly pointed out in the written description and claims hereof.

A first embodiment of the present invention is directed to a method oftreating atrial arrhythmia. The method comprises administering aneffective amount of at least one antiarrhythmic pharmaceutical agent toa patient in need thereof, such that the at least one antiarrhythmicpharmaceutical agent first enters the heart through the pulmonary veinto the left atrium.

In another aspect, the present invention is directed to a method oftreating atrial arrhythmia, e.g., tachycardia. The method comprisesadministering by inhalation an effective amount of at least oneantiarrhythmic pharmaceutical agent to a patient in need thereof,wherein an amount of the at least one antiarrhythmic pharmaceuticalagent peaks in the coronary sinus of the heart at a time ranging from 10seconds to 30 minutes from initiation of the administering.

In yet another aspect, the present invention is directed to a method ofself-diagnosing and treating atrial arrhythmia. The method comprisesself-diagnosing atrial arrhythmia by detecting at least one of shortnessof breath, heart palpitations, and above normal heart rate. The methodalso comprises self-administering by inhalation an effective amount ofat least one antiarrhythmic pharmaceutical agent within two hours of theself-diagnosing.

In another aspect, the present invention is directed to a method oftreating atrial arrhythmia, comprising administering by inhalation aneffective amount of at least one antiarrhythmic pharmaceutical agent toa patient in need thereof, wherein an electrophysiologic effect isobserved, via electrocardiography, at a time ranging from 10 seconds to30 minutes from initiation of the administering.

In still another aspect, the present invention is directed to a methodof treating atrial arrhythmia, comprising administering by inhalation aneffective amount of at least one antiarrhythmic pharmaceutical agent toa patient in need thereof, wherein a cardiac score from a monitorimplementing an arrhythmia detection algorithm shows a transition froman arrhythmic state to normal sinus rhythm in the patient at a timeranging from 10 seconds to 30 minutes from initiation of theadministering.

In yet another aspect, the present invention is directed to a method oftreating atrial arrhythmia, comprising administering by inhalation aneffective amount of at least one antiarrhythmic pharmaceutical agent toa patient in need thereof, wherein a short form-36 quality of life scoreof the patient improves at a time ranging from 10 seconds to 30 minutesfrom initiation of the administering.

In another aspect, the present invention is directed to a unit dosecomprising a unit dose receptacle and a composition within the unit dosereceptacle. The composition comprises at least one antiarrhythmicpharmaceutical agent in an amount less than or equal to an amount of thesame at least one antiarrhythmic pharmaceutical agent administeredintravenously in the arm to achieve a minimum effective amount in thecoronary sinus, and a pharmaceutically acceptable excipient.

In still another aspect, the present invention is directed to an aerosolcomprising particles having a mass median aerodynamic diameter less than10 μm. The particles comprise at least one antiarrhythmic pharmaceuticalagent in an amount less than or equal to an amount of the same at leastone antiarrhythmic pharmaceutical agent administered intravenously inthe arm to achieve a minimum effective amount in the coronary sinus, anda pharmaceutically acceptable excipient.

Yet another aspect of the present invention is directed to a kit. Thekit comprises a container containing at least one antiarrhythmicpharmaceutical agent and an aerosolization device.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention is further described in the description ofinvention that follows, in reference to the noted plurality ofnon-limiting drawings, wherein:

FIG. 1 shows how prior art intravenous drug passes through the heart andlungs before reaching coronary arteries.

FIG. 2A shows how inhaled drug of the present invention passes throughdirectly from the lungs to coronary arteries.

FIG. 2B shows how inhaled drug of the present invention passes throughthe pulmonary vein to the left atrium.

FIG. 3 shows that molecules with high Log-P values and those that havehigh lipid solubility are likely to exhibit faster absorption throughthe lung.

FIG. 4 shows a six compartment PK-PD model to compare intravenous andpulmonary delivery.

FIG. 5 shows the results of a simulation comparing intravenous andpulmonary delivery of verapamil.

FIG. 6 shows the results of a simulation comparing intravenous andpulmonary delivery of lidocaine.

FIG. 7 shows a representative study outline: effects of flecainide (FLE,n=2), diltiazem (DIL, n=2), and dofetilide (DOF, n=2) on inducedatrial-fibrillation. NSR: normal sinus rhythm.

FIG. 8 shows a representative study outline: dose-response ofintratracheal (IT) esmolol HCL (ESM, n<=2) or adenosine (ADN, n<=2) oninduced supra-ventricular tachycardia (SVT). NSR: normal sinus rhythm.IV: intravenous

FIG. 9 shows an ECG trace showing Dog in Afib prior to dosing of eithervehicle or test article.

FIG. 10 shows an ECG trace showing Dog continues to be in Afib afterpulmonary administration of vehicle (water, 3 ml).

FIG. 11 shows an ECG trace showing the Afib converting into normal sinusrhythm when a dog was administered 4 mg/kg body weight of Flecainideacetate.

FIG. 12 shows an ECG trace showing Afib converting as soon as dosingoccurred at 2 mg/kg body weight of flecainide acetate.

FIG. 13 shows an ECG trace showing Afib converting after administrationof diltiazem HCl at 0.25 mg/kg body weight.

FIG. 14 shows results from a supraventricular tachycardia model in whichPR interval and Mean Arterial blood pressure (MAP) change in time afterpulmonary administration of pulmonary diltiazem 0.25 mg/kg.

FIG. 15 shows results from the supraventricular tachycardia model inwhich PR interval and Mean Arterial blood pressure (MAP) change in timeafter intravenous administration of pulmonary diltiazem 0.25 mg/kg.

FIG. 16 shows results from the supraventricular tachycardia modelshowing effect on PR interval over time of 0.5 mg/kg body weight ofesmolol HCl administered via the lung (IT).

FIG. 17 shows results from the supraventricular tachycardia modelshowing period of AV block induced by esmolol 0.5 mg/kg administered viathe lung.

FIG. 18 shows results from the supraventricular tachycardia modelshowing period of AV block induced by esmolol 0.5 mg/kg administered viathe lung.

FIG. 19 shows results from the supraventricular tachycardia modelshowing effect on PR interval over time of 0.5 mg/kg body weight ofesmolol HCl administered via the lung (IT).

FIG. 20 shows results from the supraventricular tachycardia modelshowing period of AV block induced by esmolol 0.75 mg/kg administeredvia the lung.

DESCRIPTION OF THE INVENTION

It is to be understood that unless otherwise indicated the presentinvention is not limited to specific formulation components, drugdelivery systems, manufacturing techniques, administration steps, or thelike, as such may vary. In this regard, unless otherwise stated, areference to a compound or component includes the compound or componentby itself, as well as the compound or component in combination withother compounds or components, such as mixtures of compounds.

Before further discussion, a definition of the following terms will aidin the understanding of the present invention.

As used herein, the singular forms “a,” “an,” and “the” include pluralreferents unless the context clearly dictates otherwise. Thus, forexample, reference to “an antiarrhythmic pharmaceutical agent” includesnot only a single active agent but also a combination or mixture of twoor more different active agents.

Reference herein to “one embodiment,” “one version,” or “one aspect”shall include one or more such embodiments, versions or aspects, unlessotherwise clear from the context.

As used herein, the term “solvate” is intended to include, but not belimited to, pharmaceutically acceptable solvates.

As used herein, the term “pharmaceutically acceptable solvate” isintended to mean a solvate that retains one or more of the biologicalactivities and/or properties of the antiarrhythmic pharmaceutical agentand that is not biologically or otherwise undesirable. Examples ofpharmaceutically acceptable solvates include, but are not limited to,antiarrhythmic pharmaceutical agents in combination with water,isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid,ethanolamine, or combinations thereof.

As used herein, the term “salt” is intended to include, but not belimited to, pharmaceutically acceptable salts.

As used herein, the term “pharmaceutically acceptable salt” is intendedto mean those salts that retain one or more of the biological activitiesand properties of the free acids and bases and that are not biologicallyor otherwise undesirable. Illustrative examples of pharmaceuticallyacceptable salts include, but are not limited to, sulfates,pyrosulfates, bisulfates, sulfites, bisulfites, phosphates,monohydrogenphosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates, propionates,decanoates, caprylates, acrylates, formates, isobutyrates, caproates,heptanoates, propiolates, oxalates, malonates, succinates, suberates,sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates,benzoates, chlorobenzoates, methylbenzoates, di nitrobenzoates,hydroxybenzoates, methoxybenzoates, phthalates, sulfonates,xylenesulfonates, phenylacetates, phenyipropionates, phenylbutyrates,citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates,methanesulfonates, propanesulfonates, naphthalene-1-sulfonates,naphthalene-2-sulfonates, and mandelates.

If the antiarrhythmic pharmaceutical agent is a base, the desired saltmay be prepared by any suitable method known in the art, includingtreatment of the free base with an inorganic acid, such as hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, andthe like, or with an organic acid, such as acetic acid, maleic acid,succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid,oxalic acid, glycolic acid, salicylic acid, pyranosidyl acids such asglucuronic acid and galacturonic acid, alpha-hydroxy acids such ascitric acid and tartaric acid, amino acids such as aspartic acid andglutamic acid, aromatic acids such as benzoic acid and cinnamic acid,sulfonic acids such as p-toluenesulfonic acid and ethanesulfonic acid,or the like.

If the antiarrhythmic pharmaceutical agent is an acid, the desired saltmay be prepared by any suitable method known in the art, includingtreatment of the free acid with an inorganic or organic base, such as anamine (primary, secondary or tertiary), an alkali metal or alkalineearth metal hydroxide, or the like. Illustrative examples of suitablesalts include organic salts derived from amino acids such as glycine andarginine, ammonia, primary, secondary and tertiary amines, and cyclicamines such as piperidine, morpholine and piperazine, and inorganicsalts derived from sodium, calcium, potassium, magnesium, manganese,iron, copper, zinc, aluminum and lithium.

As used herein, “atrial arrhythmia” means an arrhythmia that affects atleast one atrium and does not include bradycardia. For instance, atrialarrhythmia may originate in and affect at least one atrium.

As used herein, “tachycardia” means an arrhythmia in which the heartbeat is too fast. For instance, tachycardia may involve a resting heartrate of over 100 beats per minute, such as greater than 110, greaterthan 120, or greater than 130 beats minute.

As used herein, the phrase “heart rhythm arrhythmia” means an arrhythmiain which the heart beat is irregular.

As used herein, the “amount of the at least one antiarrhythmicpharmaceutical agent in blood in the coronary sinus of the heart” may bemeasured by extracting a sample from the coronary sinus of the heart byusing a cannula. The amount of antiarrhythmic pharmaceutical agent inthe sample may then be determined by known means, such as bioanalyticaltechniques that employ analytical equipment such as LC-MS/MS. Thus, theamount of antiarrhythmic pharmaceutical agent in the blood in the heartmay be measured for any particular time.

As used herein, the terms “treating” and “treatment” refer to reductionin severity and/or frequency of symptoms, elimination of symptoms and/orunderlying cause, reduction in likelihood of the occurrence of symptomsand/or underlying cause, and/or remediation of damage. Thus, “treating”a patient with an active agent as provided herein includes prevention ofa particular condition, disease, or disorder in a susceptible individualas well as treatment of a clinically symptomatic individual.

As used herein, “nominal amount” refers to the amount contained withinthe unit dose receptacle(s) that are administered.

As used herein, “effective amount” refers to an amount covering boththerapeutically effective amounts and prophylactically effectiveamounts.

As used herein, a “therapeutically effective amount” of an active agentrefers to an amount that is effective to achieve a desired therapeuticresult. A therapeutically effective amount of a given active agent willtypically vary with respect to factors such as the type and severity ofthe disorder or disease being treated and the age, gender, and weight ofthe patient.

Unless otherwise specified, the term “therapeutically effective amount”includes a “prophylactically effective amount,” i.e., an amount ofactive agent that is effective to prevent the onset or recurrence of aparticular condition, disease, or disorder in a susceptible individual.

As used herein, the phrase “minimum effective amount” means the minimumamount necessary to achieve an effective amount.

As used herein, “mass median diameter” or “MMD” refers to the mediandiameter of a plurality of particles, typically in a polydisperseparticle population, i.e., consisting of a range of particle sizes. MMDvalues as reported herein are determined by laser diffraction (SympatecHelos, Clausthal-Zellerfeld, Germany), unless the context indicatesotherwise. For instance, for powders the samples are added directly tothe feeder funnel of the Sympatec RODOS dry powder dispersion unit. Thiscan be achieved manually or by agitating mechanically from the end of aVIBRI vibratory feeder element. Samples are dispersed to primaryparticles via application of pressurized air (2 to 3 bar), with vacuumdepression (suction) maximized for a given dispersion pressure.Dispersed particles are probed with a 632.8 nm laser beam thatintersects the dispersed particles' trajectory at right angles. Laserlight scattered from the ensemble of particles is imaged onto aconcentric array of photomultiplier detector elements using areverse-Fourier lens assembly. Scattered light is acquired intime-slices of 5 ms. Particle size distributions are back-calculatedfrom the scattered light spatial/intensity distribution using aproprietary algorithm.

As used herein, “geometric diameter” refers to the diameter of a singleparticle, as determined by microscopy, unless the context indicatesotherwise.

As used herein, “mass median aerodynamic diameter” or “MMAD” refers tothe median aerodynamic size of a plurality of particles or particles,typically in a polydisperse population. The “aerodynamic diameter” isthe diameter of a unit density sphere having the same settling velocity,generally in air, as a powder and is therefore a useful way tocharacterize an aerosolized powder or other dispersed particle orparticle formulation in terms of its settling behavior. The aerodynamicdiameter encompasses particle or particle shape, density, and physicalsize of the particle or particle. As used herein, MMAD refers to themedian of the aerodynamic particle or particle size distribution ofaerosolized particles determined by cascade impaction, unless thecontext indicates otherwise.

As used herein, the term “emitted dose” or “ED” refers to an indicationof the delivery of particles from an aerosolization device after anactuation or dispersion event from a unit dose receptacle or reservoir.ED is defined as the ratio of the dose delivered by an inhaler device tothe nominal dose (i.e., the mass of powder or liquid per unit doseplaced into a suitable inhaler device prior to firing). The ED is anexperimentally determined amount, and may be determined using an invitro system that mimics patient dosing. For instance, to determine anED value for a dry powder, a nominal dose of dry powder is placed into aTurbospin® DPI device (PH&T, Italy), described in U.S. Pat. Nos.4,069,819 and 4,995,385, which are incorporated herein by reference intheir entireties. The Turbospin® DPI is actuated, dispersing the powder.The resulting aerosol cloud is then drawn from the device by vacuum (30L/min) for 2.5 seconds after actuation, at which point it is captured ona tared glass fiber filter (Gelman, 47 mm diameter) attached to thedevice mouthpiece. The amount of powder that reaches the filterconstitutes the delivered dose. For example, for a capsule containing 5mg of dry powder, capture of 4 mg of powder on the tared filter wouldindicate an ED of 80% (=4 mg (delivered dose)/5 mg (nominal dose)).

As used herein, “passive dry powder inhaler” refers to an inhalationdevice that relies upon a patient's inspiratory effort to disperse andaerosolize a pharmaceutical composition contained within the device in areservoir or in a unit dose form and does not include inhaler deviceswhich comprise a means for providing energy, such as pressurized gas andvibrating or rotating elements, to disperse and aerosolize the drugcomposition.

As used herein, “active dry powder inhaler” refers to an inhalationdevice that does not rely solely on a patient's inspiratory effort todisperse and aerosolize a pharmaceutical composition contained withinthe device in a reservoir or in a unit dose form and does includeinhaler devices that comprise a means for providing energy to disperseand aerosolize the drug composition, such as pressurized gas andvibrating or rotating elements.

By a “pharmaceutically acceptable” component is meant a component thatis not biologically or otherwise undesirable, i.e., the component may beincorporated into a pharmaceutical formulation of the invention andadministered to a patient as described herein without causing anysignificant undesirable biological effects or interacting in adeleterious manner with any of the other components of the formulationin which it is contained. When the term “pharmaceutically acceptable” isused to refer to an excipient, it is generally implied that thecomponent has met the required standards of toxicological andmanufacturing testing or that it is included on the Inactive IngredientGuide prepared by the U.S. Food and Drug Administration.

As used herein, “P wave” represents the wave of depolarization thatspreads from the SA node throughout the atria, and is usually 0.08 to0.1 seconds (80-100 ms) in duration.

As used herein, “short form-36 quality of life” means the Short Form 36(SF-36) survey of patient health (updated August 2005). The SF-36consists of eight scaled scores, which are the sums of the questions intheir section. Each scale is directly transformed into a 0-100 scale onthe assumption that each question carries equal weight. The eightsections are: (1) vitality; (2) physical functioning; (3) bodily pain;(4) general health perceptions; (5) physical role functioning; (6)emotional role functioning; (7) social role functioning; and (8) mentalhealth.

As used herein, “preservative” means cresols and benzoates. Thus,“substantially preservative-free” means that a composition does notinclude a substantial amount of any cresols and/or benzoates. Forinstance, “substantially preservative-free” compositions comprise lessthan 1 wt %, such as less than 0.5 wt %, less than 0.4 wt %, less than0.3 wt %, less than 0.2 wt %, or less than 0.1 wt %, of preservative. Ofcourse, “preservative-free” means that no preservative is present.

As used herein, “substantially tasteless” means a composition that hassubstantially little to no taste upon initial ingestion.

As an overview, the present invention relates to methods of treatingatrial arrhythmia. The methods may comprise administering an effectiveamount of at least one antiarrhythmic pharmaceutical agent to a patientin need thereof, such that the at least one antiarrhythmicpharmaceutical agent first enters the heart through the pulmonary veinto the left atrium.

In one aspect, a method of treating atrial arrhythmia comprisesadministering by inhalation an effective amount of at least oneantiarrhythmic pharmaceutical agent to a patient in need thereof,wherein an amount of the at least one antiarrhythmic pharmaceuticalagent peaks in the coronary sinus of the heart at a time ranging from 10seconds to 30 minutes from initiation of the administering.

In yet another aspect, the present invention is directed to a method ofself-diagnosing and treating atrial arrhythmia. The method comprisesself-diagnosing atrial arrhythmia by detecting at least one of shortnessof breath, heart palpitations, and above normal heart rate. The methodalso comprises self-administering by inhalation an effective amount ofat least one antiarrhythmic pharmaceutical agent within two hours of theself-diagnosing.

In another aspect, a method of treating atrial arrhythmia comprisesadministering by inhalation an effective amount of at least oneantiarrhythmic pharmaceutical agent to a patient in need thereof,wherein an electrophysiologic effect is observed, viaelectrocardiography, at a time ranging from 10 seconds to 30 minutesfrom initiation of the administering.

In still another aspect, a method of treating atrial arrhythmiacomprises administering by inhalation an effective amount of at leastone antiarrhythmic pharmaceutical agent to a patient in need thereof,wherein a cardiac score from a monitor implementing an arrhythmiadetection algorithm shows a transition from an arrhythmic state tonormal sinus rhythm in the patient at a time ranging from 10 seconds to30 minutes from initiation of the administering.

In yet another aspect, a method of treating atrial arrhythmia comprisesadministering by inhalation an effective amount of at least oneantiarrhythmic pharmaceutical agent to a patient in need thereof,wherein a short form-36 quality of life score of the patient improves ata time ranging from 10 seconds to 30 minutes from initiation of theadministering.

In another aspect, a unit dose comprises a unit dose receptacle and acomposition within the unit dose receptacle. The composition comprisesat least one antiarrhythmic pharmaceutical agent in an amount less thanor equal to an amount of the same at least one antiarrhythmicpharmaceutical agent administered intravenously in the arm to achieve aminimum effective amount in the coronary sinus, and a pharmaceuticallyacceptable excipient.

In still another aspect, an aerosol comprises particles having a massmedian aerodynamic diameter less than 10 μm. The particles comprise atleast one antiarrhythmic pharmaceutical agent in an amount less than orequal to an amount of the same at least one antiarrhythmicpharmaceutical agent administered intravenously in the arm to achieve aminimum effective amount in the coronary sinus, and a pharmaceuticallyacceptable excipient.

In yet another aspect, a kit comprises a container containing at leastone antiarrhythmic pharmaceutical agent and an aerosolization device.

In certain embodiments, the present invention includes“pharmaco-rescue-therapies” to provide fast cardioversion in patientswith atrial arrhythmias like Paroxysmal Ventricular Tachycardia (PSVT),and Paroxysmal Atrial Fibrillation (PAF). The pharmaco-rescue-therapiesare usually intended for self-administration of the medicine byinhalation.

Inhalation is the shortest route for a drug to reach the heart, nextonly to intracardial injection, as shown in FIGS. 2A and 2B. Drugsdelivered by inhalation generally exhibit “pulsatile pharmacokinetics”of transient high drug concentrations, followed by dilution tosub-therapeutic levels. This characteristic is expected to reduce muchof the dose dependent pro-arrhythmia and QT prolongation seen with bothoral and IV therapies. See FELDMAN et al., “Analysis of CoronaryResponse to Various Doses of Intracoronary Nitroglycerin,” Circulation,66:321-327 (1982); and BARBATO et al., “Adrenergic Receptors in HumanAtherosclerotic Coronary Arteries,” Circulation, 111:288-294 (2005).

Thus, in some embodiments, the present invention involves a rapid actinginhaled product with a fast onset of action compared to oral medicine.The product is expected to be at least as fast as intravenous medicine.In some embodiments, an amount of the at least one antiarrhythmicpharmaceutical agent peaks in the coronary sinus of the heart at a timeranging from 10 seconds to 30 minutes, such as 30 seconds to 20 minutes,1 minute to 10 minutes, 2 minutes to 8 minutes, or 2.5 minutes to 5minutes, from initiation of the administering. In certain embodiments,an electrophysiologic effect is observed, via electrocardiography, at atime ranging from 10 seconds to 30 minutes, such as 30 seconds to 20minutes, 1 minute to 10 minutes, 2 minutes to 8 minutes, or 2.5 minutesto 5 minutes, from initiation of the administering. In some embodiments,a cardiac score from a monitor implementing an arrhythmia detectionalgorithm shows a transition from an arrhythmic state to normal sinusrhythm in the patient at a time ranging from 10 seconds to 30 minutes,such as 30 seconds to 20 minutes, 1 minute to 10 minutes, 2 minutes to 8minutes, or 2.5 minutes to 5 minutes, from initiation of theadministering. In some embodiments, a short form-36 quality of lifescore of the patient improves at a time ranging from 10 seconds to 30minutes, such as 30 seconds to 20 minutes, 1 minute to 10 minutes, 2minutes to 8 minutes, or 2.5 minutes to 5 minutes, from initiation ofthe administering. In certain embodiments, the patient has normal sinusrhythm within 30 minutes, such as within 10 minutes, of initiating theadministering.

In some aspects, the present invention involves low doses that are safeand effective. Other aspects typically involve low premature metabolismand low drug-drug interaction.

The present invention includes non-invasive drug delivery to the heart.The lung is shortest route for drug to heart with minimal dilution nextto intra-cardial injection. Drugs delivered via the lung have a fastonset action compared to those delivered via the oral route. PipelineInsights: Antiarrhythmics, Datamonitor (06/2006). Pulmonary drugdelivery to the heart is at least equivalent to a portable intravenousinjection. Inhaled drugs (e.g., verapamil, diltiazem, lidocaine,ibutilide, procainamide, and propafenone) are expected to exhibit“pulsatile pharmacokinetics” of transient high drug concentrations,followed by dilution to sub-therapeutic levels.

Existing cardiovascular drugs tend to be small molecules with high lipidsolubility. These lipid soluble molecules (e.g., diltiazem, verapamil,ibutilide, propafenone) are expected to have a high pulmonarybioavailability and fast rate of pulmonary absorption. This ensures thatthey reach the heart through the pulmonary veins.

The pulsatile pharmacokinetic behavior of the drugs show that the drugis diluted within a few seconds of reaching effective concentrations inthe heart and is diluted to sub-therapeutic levels in the volume of theblood. This characteristic will minimize drug-drug interactions thatproduce significant toxicological responses normally seen at steadystate.

Thus, in certain embodiments, the present invention relates to achievingtransient high drug concentrations in the heart that effect rate andrhythm changes in the heart within a short period of time allowing fortreatment of episodic arrhythmias such as paroxysmal atrial arrhythmias.

The results of the invention are surprising and unexpected. In thisregard, the antiarrhythmic pharmaceutical agents pass through the lungsquickly. For instance, verapamil and diltiazem will ionize if in saltform, so the base will pass through the lungs quickly. In some aspects,the methods of the present invention take advantage of fast onset ofaction, high drug bioavailability, and fast absorption through the lung.Most cardiovascular drugs are small molecules that have high lipidsolubility and are therefore expected to have high pulmonarybioavailability and a fast rate of absorption. FIG. 3 shows the log-pvalues and lipid solubility of exemplary cardiovascular molecules alongwith their expected high pulmonary bioavailability.

Another reason why the results of the present invention are surprisingand unexpected involves the rate at which the antiarrhythmicpharmaceutical agents pass through the heart. While a skilled artisanmight expect the rate to be too fast, modeling indicates that the drugwill not pass through the heart too fast. Thus, a therapeutic effect isachieved despite fast pass-through and despite only one pass-through attherapeutic levels.

In view of the above, in one or more embodiments of the invention, acomposition comprises an antiarrhythmic pharmaceutical agent. Examplesof antiarrhythmic pharmaceutical agents include, but are not limited to,class Ia (sodium channel blockers, intermediateassociation/dissociation), class Ib (sodium channel blockers, fastassociation/dissociation), class Ic (sodium channel blocker, slowassociation/dissociation), class II (beta blockers), class III(potassium channel blockers), class IV (calcium channel blockers), andclass V (unknown mechanisms) antiarrhythmics.

Class Ia antiarrhythmics include, but are not limited to, quinidine,procainamide, and disopyramide. Class Ib antiarrhythmics include, butare not limited to, lidocaine, tocainide, phenytoin, moricizine, andmexiletine. Class Ic antiarrhythmics include, but are not limited to,flecainide, propafenone, and moricizine. Class H antiarrhythmicsinclude, but are not limited to, propranolol, acebutolol, soltalol,esmolol, timolol, metoprolol, and atenolol. Class III antiarrhythmicsinclude, but are not limited to, amiodarone, sotalol, bretylium,ibutilide, E-4031 (methanesulfonamide), vernakalant, and dofetilide.Class IV antiarrhythmics include, but are not limited to, bepridil,nitrendipine, amlodipine, isradipine, nifedipine, nicardipine,verapamil, and diltiazem. Class V antiarrhythmics include, but are notlimited to, digoxin and adenosine.

The present invention also includes derivatives of the aboveantiarrhythmic pharmaceutical agents such as solvates, salts, solvatedsalts, esters, amides, hydrazides, N-alkyls, and/or N-amino acyls.Examples of ester derivatives include, but are not limited to, methylesters, choline esters, and dimethylaminopropyl esters. Examples ofamide derivatives include, but are not limited to, primary, secondary,and tertiary amides. Examples of hydrazide derivatives include, but arenot limited to, N-methylpiperazine hydrazides. Examples of N-alkylderivatives include, but are not limited to, N′,N′,N′-trimethyl andN′,N′-dimethylaminopropyl succininimidyl derivatives of antiarrhythmicpharmaceutical agent methyl esters. Examples of N-aminoacyl derivativesinclude, but are not limited to, N-ornithyl-, N-diaminopropionyl-,N-lysil-, N-hexamethyllysil-, and N-piperdine-propionyl- orN′,N′-methyl-1-piperazine-propionyl-antiarrhythmic pharmaceutical agentmethyl esters.

The antiarrhythmic pharmaceutical agents may exist as singlestereoisomers, racemates, and/or mixtures of enantiomers, and/ordiastereomers. All such single stereoisomers, racemates, and mixturesthereof are intended to be within the scope of the present invention.These various forms of the compounds may be isolated/prepared by methodsknown in the art.

The antiarrhythmic pharmaceutical agents of the present invention may beprepared in a racemic mixture (i.e., mixture of isomers) that containsmore than 50%, preferably at least 75%, and more preferably at least 90%of the desired isomer (i.e., 80% enantiomeric or diastereomeric excess).According to particularly preferred embodiments, the compounds of thepresent invention are prepared in a form that contains at least 95% (90%e.e. or d.e.), even more preferably at least 97.5% (95% e.e. or d.e.),and most preferably at least 99% (98% e.e. or d.e.) of the desiredisomer. Compounds identified herein as single stereoisomers are meant todescribe compounds used in a form that contains more than 50% of asingle isomer. By using known techniques, these compounds may beisolated in any of such forms by slightly varying the method ofpurification and/or isolation from the solvents used in the syntheticpreparation of such compounds.

The pharmaceutical composition according to one or more embodiments ofthe invention may comprise one or more antiarrhythmic pharmaceuticalagents and, optionally, one or more other active ingredients and,optionally, one or more pharmaceutically acceptable excipients. Forexample, the pharmaceutical composition may comprise neat particles ofantiarrhythmic pharmaceutical agent, may comprise neat particles ofantiarrhythmic pharmaceutical agent together with other particles,and/or may comprise particles comprising antiarrhythmic pharmaceuticalagent and one or more active ingredients and/or one or morepharmaceutically acceptable excipients.

Thus, the pharmaceutical composition according to one or moreembodiments of the invention may, if desired, contain a combination ofantiarrhythmic pharmaceutical agent and one or more additional activeagents. Examples of additional active agents include, but are notlimited to, agents that may be delivered through the lungs.

Additional active agents may comprise, for example, hypnotics andsedatives, psychic energizers, tranquilizers, respiratory drugs,anticonvulsants, muscle relaxants, antiparkinson agents (dopamineantagnonists), analgesics, anti-inflammatories, antianxiety drugs(anxiolytics), appetite suppressants, antimigraine agents, musclecontractants, additional anti-infectives (antivirals, antifungals,vaccines) antiarthritics, antimalarials, antiemetics, anepileptics,cytokines, growth factors, anti-cancer agents, antithrombotic agents,antihypertensives, cardiovascular drugs, antiarrhythmics, antioxidants,anti-asthma agents, hormonal agents including contraceptives,sympathomimetics, diuretics, lipid regulating agents, antiandrogenicagents, antiparasitics, anticoagulants, neoplastics, antineoplastics,hypoglycemics, nutritional agents and supplements, growth supplements,antienteritis agents, vaccines, antibodies, diagnostic agents, andcontrasting agents. The additional active agent, when administered byinhalation, may act locally or systemically.

The additional active agent may fall into one of a number of structuralclasses, including but not limited to small molecules, peptides,polypeptides, proteins, polysaccharides, steroids, proteins capable ofeliciting physiological effects, nucleotides, oligonucleotides,polynucleotides, fats, electrolytes, and the like.

Examples of additional active agents suitable for use in this inventioninclude but are not limited to one or more of calcitonin, amphotericinB, erythropoietin (EPO), Factor VIII, Factor IX, ceredase, cerezyme,cyclosporin, granulocyte colony stimulating factor (GCSF),thrombopoietin (TPO), alpha-1 proteinase inhibitor, elcatonin,granulocyte macrophage colony stimulating factor (GMCSF), growthhormone, human growth hormone (HGH), growth hormone releasing hormone(GHRH), heparin, low molecular weight heparin (LMWH), interferon alpha,interferon beta, interferon gamma, interleukin-1 receptor,interleukin-2, interleukin-1 receptor antagonist, interleukin-3,interleukin-4, interleukin-6, luteinizing hormone releasing hormone(LHRH), factor IX, insulin, pro-insulin, insulin analogues (e.g.,mono-acylated insulin as described in U.S. Pat. No. 5,922,675, which isincorporated herein by reference in its entirety), amylin, C-peptide,somatostatin, somatostatin analogs including octreotide, vasopressin,follicle stimulating hormone (FSH), insulin-like growth factor (IGF),insulintropin, macrophage colony stimulating factor (M-CSF), nervegrowth factor (NGF), tissue growth factors, keratinocyte growth factor(KGF), glial growth factor (GGF), tumor necrosis factor (TNF),endothelial growth factors, parathyroid hormone (PTH), glucagon-likepeptide thymosin alpha 1, IIb/IIa inhibitor, alpha-1 antitrypsin,phosphodiesterase (PDE) compounds, VLA-4 inhibitors, bisphosponates,respiratory syncytial virus antibody, cystic fibrosis transmembraneregulator (CFFR) gene, deoxyribonuclease (DNase),bactericidal/permeability increasing protein (BPI), anti-CMV antibody,13-cis retinoic acid, oleandomycin, troleandomycin, roxithromycin,clarithromycin, davercin, azithromycin, flurithromycin, dirithromycin,josamycin, spiromycin, midecamycin, leucomycin, miocamycin, rokitamycin,andazithromycin, and swinolide A; fluoroquinolones such asciprofloxacin, ofloxacin, levofloxacin, trovafloxacin, alatrofloxacin,moxifloxicin, norfloxacin, enoxacin, grepafloxacin, gatifloxacin,lomefloxacin, sparfloxacin, temafloxacin, pefloxacin, amifloxacin,fleroxacin, tosufloxacin, prulifloxacin, irloxacin, pazufloxacin,clinafloxacin, and sitafloxacin, teicoplanin, rampolanin, mideplanin,colistin, daptomycin, gramicidin, colistimethate, polymixins such aspolymixin B, capreomycin, bacitracin, penems; penicillins includingpenicllinase-sensitive agents like penicillin G, penicillin V,penicillinase-resistant agents like methicillin, oxacillin, cloxacillin,dicloxacillin, floxacillin, nafcillin; gram negative microorganismactive agents like ampicillin, amoxicillin, and hetacillin, cillin, andgalampicillin; antipseudomonal penicillins like carbenicillin,ticarcillin, azlocillin, mezlocillin, and piperacillin; cephalosporinslike cefpodoxime, cefprozil, ceftbuten, ceftizoxime, ceftriaxone,cephalothin, cephapirin, cephalexin, cephradrine, cefoxitin,cefamandole, cefazolin, cephaloridine, cefaclor, cefadroxil,cephaloglycin, cefuroxime, ceforanide, cefotaxime, cefatrizine,cephacetrile, cefepime, cefixime, cefonicid, cefoperazone, cefotetan,cefinetazole, ceftazidime, loracarbef, and moxalactam, monobactams likeaztreonam; and carbapenems such as imipenem, meropenem, pentamidineisethiouate, lidocaine, metaproterenol sulfate, beclomethasonediprepionate, triamcinolone acetamide, budesonide acetonide,fluticasone, ipratropium bromide, flunisolide, cromolyn sodium,ergotamine tartrate and where applicable, analogues, agonists,antagonists, inhibitors, and pharmaceutically acceptable salt forms ofthe above. In reference to peptides and proteins, the invention isintended to encompass synthetic, native, glycosylated, unglycosylated,pegylated forms, and biologically active fragments, derivatives, andanalogs thereof.

Additional active agents for use in the invention further includenucleic acids, as bare nucleic acid molecules, vectors, associated viralparticles, plasmid DNA or RNA or other nucleic acid constructions of atype suitable for transfection or transformation of cells, i.e.,suitable for gene therapy including antisense. Further, an active agentmay comprise live attenuated or killed viruses suitable for use asvaccines. Other useful drugs include those listed within the Physician'sDesk Reference (most recent edition), which is incorporated herein byreference in its entirety.

When a combination of active agents is used, the agents may be providedin combination in a single species of pharmaceutical composition orindividually in separate species of pharmaceutical compositions.

The amount of antiarrhythmic pharmaceutical agent in the pharmaceuticalcomposition may vary. The amount of antiarrhythmic pharmaceuticalagent(s) is typically at least about 5 wt %, such as at least about 10wt %, at least about 20 wt %, at least about 30 wt %, at least about 40wt %, at least about 50 wt %, at least about 60 wt %, at least about 70wt %, or at least about 80 wt %, of the total amount of thepharmaceutical composition. The amount of antiarrhythmic pharmaceuticalagent(s) generally varies between about 0.1 wt % to 100 wt %, such asabout 5 wt % to about 95 wt %, about 10 wt % to about 90 wt %, about 30wt % to about 80 wt %, about 40 wt % to about 70 wt %, or about 50 wt %to about 60 wt %.

As noted above, the pharmaceutical composition may include one or morepharmaceutically acceptable excipient. Examples of pharmaceuticallyacceptable excipients include, but are not limited to, lipids, metalions, surfactants, amino acids, carbohydrates, buffers, salts, polymers,and the like, and combinations thereof.

Examples of lipids include, but are not limited to, phospholipids,glycolipids, ganglioside GM1, sphingomyelin, phosphatidic acid,cardiolipin; lipids bearing polymer chains such as polyethylene glycol,chitin, hyaluronic acid, or polyvinylpyrrolidone; lipids bearingsulfonated mono-, di-, and polysaccharides; fatty acids such as palmiticacid, stearic acid, and oleic acid; cholesterol, cholesterol esters, andcholesterol hemisuccinate.

In one or more embodiments, the phospholipid comprises a saturatedphospholipid, such as one or more phosphatidylcholines. Exemplary acylchain lengths are 16:0 and 18:0 (i.e., palmitoyl and stearoyl). Thephospholipid content may be determined by the active agent activity, themode of delivery, and other factors.

Phospholipids from both natural and synthetic sources may be used invarying amounts. When phospholipids are present, the amount is typicallysufficient to coat the active agent(s) with at least a single molecularlayer of phospholipid. In general, the phospholipid content ranges fromabout 5 wt % to about 99.9 wt %, such as about 20 wt % to about 80 wt %.

Generally, compatible phospholipids comprise those that have a gel toliquid crystal phase transition greater than about 40° C., such asgreater than about 60° C., or greater than about 80° C. The incorporatedphospholipids may be relatively long chain (e.g., C₁₆-C₂₂) saturatedlipids. Exemplary phospholipids useful in the present invention include,but are not limited to, phosphoglycerides such asdipalmitoylphosphatidylcholine, distearoylphosphatidylcholine,diarachidoylphosphatidylcholine, dibehenoylphosphatidylcholine,diphosphatidyl glycerols, short-chain phosphatidylcholines, hydrogenatedphosphatidylcholine, E-100-3 (available from Lipoid KG, Ludwigshafen,Germany), long-chain saturated phosphatidylethanolamines, long-chainsaturated phosphatidylserines, long-chain saturatedphosphatidylglycerols, long-chain saturated phosphatidylinositols,phosphatidic acid, phosphatidylinositol, and sphingomyelin.

Examples of metal ions include, but are not limited to, divalentcations, including calcium, magnesium, zinc, iron, and the like. Forinstance, when phospholipids are used, the pharmaceutical compositionmay also comprise a polyvalent cation, as disclosed in WO 01/85136 andWO 01/85137, which are incorporated herein by reference in theirentireties. The polyvalent cation may be present in an amount effectiveto increase the melting temperature (T_(m)) of the phospholipid suchthat the pharmaceutical composition exhibits a T_(m) which is greaterthan its storage temperature (T_(m)) by at least about 20° C., such asat least about 40° C. The molar ratio of polyvalent cation tophospholipid may be at least about 0.05:1, such as about 0.05:1 to about2.0:1 or about 0.25:1 to about 1.0:1. An example of the molar ratio ofpolyvalent cation:phospholipid is about 0.50:1. When the polyvalentcation is calcium, it may be in the form of calcium chloride. Althoughmetal ion, such as calcium, is often included with phospholipid, none isrequired.

As noted above, the pharmaceutical composition may include one or moresurfactants. For instance, one or more surfactants may be in the liquidphase with one or more being associated with solid particles orparticles of the composition. By “associated with” it is meant that thepharmaceutical compositions may incorporate, adsorb, absorb, be coatedwith, or be formed by the surfactant. Surfactants include, but are notlimited to, fluorinated and nonfluorinated compounds, such as saturatedand unsaturated lipids, nonionic detergents, nonionic block copolymers,ionic surfactants, and combinations thereof. It should be emphasizedthat, in addition to the aforementioned surfactants, suitablefluorinated surfactants are compatible with the teachings herein and maybe used to provide the desired preparations.

Examples of nonionic detergents include, but are not limited to,sorbitan esters including sorbitan trioleate (Span™ 85), sorbitansesquioleate, sorbitan monooleate, sorbitan monolaurate, polyoxyethylene(20) sorbitan monolaurate, and polyoxyethylene (20) sorbitan monooleate,oleyl polyoxyethylene (2) ether, stearyl polyoxyethylene (2) ether,lauryl polyoxyethylene (4) ether, glycerol esters, and sucrose esters.Other suitable nonionic detergents can be easily identified usingMcCutcheon's Emulsifiers and Detergents (McPublishing Co., Glen Rock,N.J.), which is incorporated herein by reference in its entirety.

Examples of block copolymers include, but are not limited to, diblockand triblock copolymers of polyoxyethylene and polyoxypropylene,including poloxamer 188 (Pluronic™ F-68), poloxamer 407 (Pluronic™F-127), and poloxamer 338.

Examples of ionic surfactants include, but are not limited to, sodiumsulfosuccinate, and fatty acid soaps.

Examples of amino acids include, but are not limited to hydrophobicamino acids. Use of amino acids as pharmaceutically acceptableexcipients is known in the art as disclosed in WO 95/31479, WO 96/32096,and WO 96/32149, which are incorporated herein by reference in theirentireties.

Examples of carbohydrates include, but are not limited to,monosaccharides, disaccharides, and polysaccharides. For example,monosaccharides such as dextrose (anhydrous and monohydrate), galactose,mannitol, D-mannose, sorbitol, sorbose and the like; disaccharides suchas lactose, maltose, sucrose, trehalose, and the like; trisaccharidessuch as raffinose and the like; and other carbohydrates such as starches(hydroxyethylstarch), cyclodextrins, and maltodextrins.

Examples of buffers include, but are not limited to, tris or citrate.

Examples of acids include, but are not limited to, carboxylic acids.

Examples of salts include, but are not limited to, sodium chloride,salts of carboxylic acids, (e.g., sodium citrate, sodium ascorbate,magnesium gluconate, sodium gluconate, tromethamine hydrochloride,etc.), ammonium carbonate, ammonium acetate, ammonium chloride, and thelike.

Examples of organic solids include, but are not limited to, camphor, andthe like.

The pharmaceutical composition of one or more embodiments of the presentinvention may also include a biocompatible, such as biodegradablepolymer, copolymer, or blend or other combination thereof. In thisrespect useful polymers comprise polylactides, polylactide-glycolides,cyclodextrins, polyacrylates, methylcellulose, carboxymethylcellulose,polyvinyl alcohols, polyanhydrides, polylactams, polyvinyl pyrrolidones,polysaccharides (dextrans, starches, chitin, chitosan, etc.), hyaluronicacid, proteins, (albumin, collagen, gelatin, etc.). Those skilled in theart will appreciate that, by selecting the appropriate polymers, thedelivery efficiency of the composition and/or the stability of thedispersions may be tailored to optimize the effectiveness of theantiarrhythmic pharmaceutical agent(s).

For solutions, the compositions may include one or more osmolalityadjuster, such as sodium chloride. For instance, sodium chloride may beadded to solutions to adjust the osmolality of the solution. In one ormore embodiments, an aqueous composition consists essentially of theantiarrhythmic pharmaceutical agent, the osmolality adjuster, and water.

Solutions may also comprise a buffer or a pH adjusting agent, typicallya salt prepared from an organic acid or base. Representative bufferscomprise organic acid salts of citric acid, lactic acid, ascorbic acid,gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid,or phthalic acid, Tris, tromethamine hydrochloride, or phosphatebuffers. Thus, the buffers include citrates, phosphates, phthalates, andlactates.

Besides the above mentioned pharmaceutically acceptable excipients, itmay be desirable to add other pharmaceutically acceptable excipients tothe pharmaceutical composition to improve particle rigidity, productionyield, emitted dose and deposition, shelf-life, and patient acceptance.Such optional pharmaceutically acceptable excipients include, but arenot limited to: coloring agents, taste masking agents, buffers,hygroscopic agents, antioxidants, and chemical stabilizers. Further,various pharmaceutically acceptable excipients may be used to providestructure and form to the particle compositions (e.g., latex particles).In this regard, it will be appreciated that the rigidifying componentscan be removed using a post-production technique such as selectivesolvent extraction.

The pharmaceutical compositions of one or more embodiments of thepresent invention often lack taste. In this regard, although tastemasking agents are optionally included within the composition, thecompositions often do not include a taste masking agent and lack tasteeven without a taste masking agent.

The pharmaceutical compositions may also include mixtures ofpharmaceutically acceptable excipients. For instance, mixtures ofcarbohydrates and amino acids are within the scope of the presentinvention.

The compositions of one or more embodiments of the present invention maytake various forms, such as solutions, dry powders, reconstitutedpowders, suspensions, or dispersions comprising a non-aqueous phase,such as propellants (e.g., chlorofluorocarbon, hydrofluoroalkane).

The solutions of the present invention are typically clear. In thisregard, many of the antiarrhythmic pharmaceutical agents of the presentinvention are water soluble.

In some embodiments, the isotonicity of the solution ranges fromisotonic to physiologic isotonicity. Physiologic isotonicity is theisotonicity of physiological fluids.

The compositions typically have a pH ranging from 3.5 to 8.0, such asfrom 4.0 to 7.5, or 4.5 to 7.0, or 5.0 to 6.5.

For dry powders, the moisture content is typically less than about 15 wt%, such as less than about 10 wt %, less than about 5 wt %, less thanabout 2 wt %, less than about 1 wt %, or less than about 0.5 wt %. Suchpowders are described in WO 95/24183, WO 96/32149, WO 99/16419, WO99/16420, and WO 99/16422, which are incorporated herein by reference intheir entireties.

In one version, the pharmaceutical composition comprises antiarrhythmicpharmaceutical agent incorporated into a phospholipid matrix. Thepharmaceutical composition may comprise phospholipid matrices thatincorporate the active agent and that are in the form of particles thatare hollow and/or porous microstructures, as described in theaforementioned WO 99/16419, WO 99/16420, WO 99/16422, WO 01/85136, andWO 01/85137, which are incorporated herein by reference in theirentireties. The hollow and/or porous microstructures are useful indelivering the antiarrhythmic pharmaceutical agent to the lungs becausethe density, size, and aerodynamic qualities of the hollow and/or porousmicrostructures facilitate transport into the deep lungs during a user'sinhalation. In addition, the phospholipid-based hollow and/or porousmicrostructures reduce the attraction forces between particles, makingthe pharmaceutical composition easier to deagglomerate duringaerosolization and improving the flow properties of the pharmaceuticalcomposition making it easier to process.

In one version, the pharmaceutical composition is composed of hollowand/or porous microstructures having a bulk density less than about 1.0g/cm³, less than about 0.5 g/cm³, less than about 0.3 g/cm³, less thanabout 0.2 g/cm³, or less than about 0.1 g/cm³. By providing low bulkdensity particles or particles, the minimum powder mass that can befilled into a unit dose container is reduced, which eliminates the needfor carrier particles. That is, the relatively low density of thepowders of one or more embodiments of the present invention provides forthe reproducible administration of relatively low dose pharmaceuticalcompounds. Moreover, the elimination of carrier particles willpotentially reduce throat deposition and any “gag” effect or coughing,since large carrier particles, e.g., lactose particles, will impact thethroat and upper airways due to their size.

In some aspects, the present invention involves high rugosity particles.For instance, the particles may have a rugosity of greater than 2, suchas greater than 3, or greater than 4, and the rugosity may range from 2to 15, such as 3 to 10.

In one version, the pharmaceutical composition is in dry powder form andis contained within a unit dose receptacle which may be inserted into ornear the aerosolization apparatus to aerosolize the unit dose of thepharmaceutical composition. This version is useful in that the drypowder form may be stably stored in its unit dose receptacle for a longperiod of time. In some examples, pharmaceutical compositions of one ormore embodiments of the present invention may be stable for at least 2years. In some versions, no refrigeration is required to obtainstability. In other versions, reduced temperatures, e.g., at 2-8° C.,may be used to prolong stable storage. In many versions, the storagestability allows aerosolization with an external power source.

It will be appreciated that the pharmaceutical compositions disclosedherein may comprise a structural matrix that exhibits, defines orcomprises voids, pores, defects, hollows, spaces, interstitial spaces,apertures, perforations or holes. The absolute shape (as opposed to themorphology) of the perforated microstructure is generally not criticaland any overall configuration that provides the desired characteristicsis contemplated as being within the scope of the invention. Accordingly,some embodiments comprise approximately spherical shapes. However,collapsed, deformed or fractured particles are also compatible.

In one version, the antiarrhythmic pharmaceutical agent is incorporatedin a matrix that forms a discrete particle, and the pharmaceuticalcomposition comprises a plurality of the discrete particles. Thediscrete particles may be sized so that they are effectivelyadministered and/or so that they are available where needed. Forexample, for an aerosolizable pharmaceutical composition, the particlesare of a size that allows the particles to be aerosolized and deliveredto a user's respiratory tract during the user's inhalation.

The matrix material may comprise a hydrophobic or a partiallyhydrophobic material. For example, the matrix material may comprise alipid, such as a phospholipid, and/or a hydrophobic amino acid, such asleucine or tri-leucine. Examples of phospholipid matrices are describedin WO 99/16419, WO 99/16420, WO 99/16422, WO 01/85136, and WO 01/85137and in U.S. Pat. Nos. 5,874,064; 5,855,913; 5,985,309; 6,503,480; and7,473,433, and in U.S. Published App. No. 20040156792, all of which areincorporated herein by reference in their entireties. Examples ofhydrophobic amino acid matrices are described in U.S. Pat. Nos.6,372,258; 6,358,530; and 7,473,433, which are incorporated herein byreference in their entireties.

When phospholipids are utilized as the matrix material, thepharmaceutical composition may also comprise a polyvalent cation, asdisclosed in WO 01/85136 and WO 01/85137, which are incorporated hereinby reference in their entireties.

According to another embodiment, release kinetics of the compositioncontaining antiarrhythmic pharmaceutical agent(s) is controlled.According to one or more embodiments, the compositions of the presentinvention provide immediate release of the antiarrhythmic pharmaceuticalagent(s). Alternatively, the compositions of other embodiments of thepresent invention may be provided as non-homogeneous mixtures of activeagent incorporated into a matrix material and unincorporated activeagent in order to provide desirable release rates of antiarrhythmicpharmaceutical agent According to this embodiment, antiarrhythmicpharmaceutical agents formulated using the emulsion-based manufacturingprocess of one or more embodiments of the present invention have utilityin immediate release applications when administered to the respiratorytract. Rapid release is facilitated by: (a) the high specific surfacearea of the low density porous powders; (b) the small size of the drugcrystals that are incorporated therein, and; (c) the low surface energyof the particles.

Alternatively, it may be desirable to engineer the particle matrix sothat extended release of the active agent(s) is effected. This may beparticularly desirable when the active agent(s) is rapidly cleared fromthe lungs or when sustained release is desired. For example, the natureof the phase behavior of phospholipid molecules is influenced by thenature of their chemical structure and/or preparation methods inspray-drying feedstock and drying conditions and other compositioncomponents utilized. In the case of spray-drying of active agent(s)solubilized within a small unilamellar vesicle (SUV) or multilamellarvesicle (MLV), the active agent(s) are encapsulated within multiplebilayers and are released over an extended time.

In contrast, spray-drying of a feedstock comprised of emulsion dropletsand dispersed or dissolved active agent(s) in accordance with theteachings herein leads to a phospholipid matrix with less long-rangeorder, thereby facilitating rapid release. While not being bound to anyparticular theory, it is believed that this is due in part to the factthat the active agent(s) are never formally encapsulated in thephospholipid, and the fact that the phospholipid is initially present onthe surface of the emulsion droplets as a monolayer (not a bilayer as inthe case of liposomes). The spray-dried particles prepared by theemulsion-based manufacturing process of one or more embodiments of thepresent invention often have a high degree of disorder. Also, thespray-dried particles typically have low surface energies, where valuesas low as 20 mN/m have been observed for spray-dried DSPC particles(determined by inverse gas chromatography). Small angle X-ray scattering(SAXS) studies conducted with spray-dried phospholipid particles havealso shown a high degree of disorder for the lipid, with scatteringpeaks smeared out, and length scales extending in some instances onlybeyond a few nearest neighbors.

It should be noted that a matrix having a high gel to liquid crystalphase transition temperature is not sufficient in itself to achievesustained release of the active agent(s). Having sufficient order forthe bilayer structures is also important for achieving sustainedrelease. To facilitate rapid release, an emulsion-system of highporosity (high surface area), and minimal interaction between the drugsubstance and phospholipid may be used. The pharmaceutical compositionformation process may also include the additions of other compositioncomponents (e.g., small polymers such as Pluronic F-68; carbohydrates,salts, hydrotropes) to break the bilayer structure are alsocontemplated.

To achieve a sustained release, incorporation of the phospholipid inbilayer form may be used, especially if the active agent is encapsulatedtherein. In this case increasing the T_(m) of the phospholipid mayprovide benefit via incorporation of divalent counterions orcholesterol. As well, increasing the interaction between thephospholipid and drug substance via the formation of ion-pairs(negatively charged active+steaylamine, positively chargedactive+phosphatidylglycerol) would tend to decrease the dissolutionrate. If the active is amphiphilic, surfactant/surfactant interactionsmay also slow active dissolution.

The addition of divalent counterions (e.g., calcium or magnesium ions)to long-chain saturated phosphatidylcholines results in an interactionbetween the negatively charged phosphate portion of the zwitterionicheadgroup and the positively charged metal ion. This results in adisplacement of water of hydration and a condensation of the packing ofthe phospholipid lipid headgroup and acyl chains. Further, this resultsin an increase in the Tm of the phospholipid. The decrease in headgrouphydration can have profound effects on the spreading properties ofspray-dried phospholipid particles on contact with water. A fullyhydrated phosphatidylcholine molecule will diffuse very slowly to adispersed crystal via molecular diffusion through the water phase. Theprocess is exceedingly slow because the solubility of the phospholipidin water is very low (about 10⁻¹⁰ mol/L for DPPC). Prior art attempts toovercome this phenomenon include homogenizing the crystals in thepresence of the phospholipid. In this case, the high degree of shear andradius of curvature of the homogenized crystals facilitates coating ofthe phospholipid on the crystals. In contrast, “dry” phospholipidpowders according to one or more embodiments of this invention canspread rapidly when contacted with an aqueous phase, thereby coatingdispersed crystals without the need to apply high energies.

For example, upon reconstitution, the surface tension of spray-driedDSPC/Ca mixtures at the air/water interface decreases to equilibriumvalues (about 20 mN/m) as fast as a measurement can be taken. Incontrast, liposomes of DSPC decrease the surface tension (about 50 mN/m)very little over a period of hours, and it is likely that this reductionis due to the presence of hydrolysis degradation products such as freefatty acids in the phospholipid. Single-tailed fatty acids can diffusemuch more rapidly to the air/water interface than can the hydrophobicparent compound. Hence, the addition of calcium ions tophosphatidylcholines can facilitate the rapid encapsulation ofcrystalline drugs more rapidly and with lower applied energy.

In another version, the pharmaceutical composition comprises low densityparticles achieved by co-spray-drying nanocrystals with aperfluorocarbon-in-water emulsion. The nanocrystals may be formed byprecipitation and may, e.g., range in size from about 45 μm to about 80μm. Examples of perfluorocarbons include, but are not limited to,perfluorohexane, perfluorooctyl bromide, perfluorooctyl ethane,perfluorodecalin, perfluorobutyl ethane.

In accordance with the teachings herein the particles may be provided ina “dry” state. That is, in one or more embodiments, the particles willpossess a moisture content that allows the powder to remain chemicallyand physically stable during storage at ambient or reduced temperatureand remain dispersible. In this regard, there is little or no change inprimary particle size, content, purity, and aerodynamic particle sizedistribution.

As such, the moisture content of the particles is typically less thanabout 10 wt %, such as less than about 6 wt %, less than about 3 wt %,or less than about 1 wt %. The moisture content is, at least in part,dictated by the composition and is controlled by the process conditionsemployed, e.g., inlet temperature, feed concentration, pump rate, andblowing agent type, concentration and post drying. Reduction in boundwater leads to significant improvements in the dispersibility andflowability of phospholipid based powders, leading to the potential forhighly efficient delivery of powdered lung surfactants or particlecomposition comprising active agent dispersed in the phospholipid. Theimproved dispersibility allows simple passive DPI devices to be used toeffectively deliver these powders.

Yet another version of the pharmaceutical composition includes particlecompositions that may comprise, or may be partially or completely coatedwith, charged species that prolong residence time at the point ofcontact or enhance penetration through mucosae. For example, anioniccharges are known to favor mucoadhesion while cationic charges may beused to associate the formed particle with negatively charged bioactiveagents such as genetic material. The charges may be imparted through theassociation or incorporation of polyanionic or polycationic materialssuch as polyacrylic acids, polylysine, polylactic acid, and chitosan.

In some versions, the pharmaceutical composition comprises particleshaving a mass median diameter less than about 20 μm, such as less thanabout 10 μm, less than about 7 μm, or less than about 5 μm. Theparticles may have a mass median aerodynamic diameter ranging from about1 μm to about 6 μm, such as about 1.5 μm to about 5 μm, or about 2 μm toabout 4 μm. If the particles are too large, a larger percentage of theparticles may not reach the lungs. If the particles are too small, alarger percentage of the particles may be exhaled.

Unit doses of the pharmaceutical compositions may be contained in acontainer. Examples of containers include, but are not limited to,syringes, capsules, blow fill seal, blisters, vials, ampoules, orcontainer closure systems made of metal, polymer (e.g., plastic,elastomer), glass, or the like. For instance, the vial may be acolorless Type I borosilicate glass ISO 6R 10 mL vial with a chlorobutylrubber siliconized stopper, and rip-off type aluminum cap with coloredplastic cover.

The container may be inserted into an aerosolization device. Thecontainer may be of a suitable shape, size, and material to contain thepharmaceutical composition and to provide the pharmaceutical compositionin a usable condition. For example, the capsule or blister may comprisea wall which comprises a material that does not adversely react with thepharmaceutical composition. In addition, the wall may comprise amaterial that allows the capsule to be opened to allow thepharmaceutical composition to be aerosolized. In one version, the wallcomprises one or more of gelatin, hydroxypropyl methylcellulose (HPMC),polyethyleneglycol-compounded HPMC, hydroxyproplycellulose, agar,aluminum foil, or the like. In one version, the capsule may comprisetelescopically adjoining sections, as described for example in U.S. Pat.No. 4,247,066 which is incorporated herein by reference in its entirety.The size of the capsule may be selected to adequately contain the doseof the pharmaceutical composition. The sizes generally range from size 5to size 000 with the outer diameters ranging from about 4.91 mm to 9.97mm, the heights ranging from about 11.10 mm to about 26.14 mm, and thevolumes ranging from about 0.13 mL to about 1.37 mL, respectively.Suitable capsules are available commercially from, for example, ShionogiQualicaps Co. in Nara, Japan and Capsugel in Greenwood, S.C. Afterfilling, a top portion may be placed over the bottom portion to form acapsule shape and to contain the powder within the capsule, as describedin U.S. Pat. Nos. 4,846,876 and 6,357,490, and in WO 00/07572, which areincorporated herein by reference in their entireties. After the topportion is placed over the bottom portion, the capsule can optionally bebanded.

For solutions, the amount of the composition in the unit dose typicallyranges from about 2 ml to about 15 ml, such as from about 3 ml to about10 ml, about 4 ml to about 8 ml, or about 5 ml to about 6 ml.

The compositions of the present invention may be made by any of thevarious methods and techniques known and available to those skilled inthe art.

For instance, a solution of antiarrhythmic pharmaceutical agent may bemade using the following procedure. Typically, manufacturing equipmentis sterilized before use. A portion of the final volume, e.g., 70%, ofsolvent, e.g., water for injection, may be added into a suitablecontainer. Antiarrhythmic pharmaceutical agent may then be added. Theantiarrhythmic pharmaceutical agent may be mixed until dissolved.Additional solvent may be added to make up the final batch volume. Thebatch may be filtered, e.g., through a 0.2 μm filter into a sterilizedreceiving vessel. Filling components may be sterilized before use infilling the batch into vials, e.g., 10 ml vials.

As an example, the above-noted sterilizing may include the following. A5 liter type 1 glass bottle and lid may be placed in an autoclave bagand sterilized at elevated temperature, e.g., 121° C. for 15 minutes,using an autoclave. Similarly, vials may be placed into suitable racks,inserted into an autoclave bag, and sterilized at elevated temperature,e.g., 121° C. for 15 minutes, using an autoclave. Also similarly,stoppers may be placed in an autoclave bag and sterilized at elevatedtemperature, e.g., 121° C. for 15 minutes, using an autoclave. Beforesterilization, sterilizing filters may be attached to tubing, e.g., a 2mm length of 7 mm×13 mm silicone tubing. A filling line may be preparedby placed in an autoclave bag and sterilized at elevated temperature,e.g., 121° C. for 15 minutes, using an autoclave.

The above-noted filtration may involve filtration into a laminar flowwork area. The receiving bottle and filters may be set up in the laminarflow work area.

The above-noted filling may also be conducted under laminar flowprotection. The filling line may be unwrapped and placed into thereceiving bottle. The sterilized vials and stoppers may be unwrappedunder laminar flow protection. Each vial may be filled, e.g., to atarget fill of 5 g, and stoppered. A flip off collar may be applied toeach vial. The sealed vials may be inspected for vial leakage, correctoverseals, and cracks.

As another example, an antiarrhythmic may be prepared by lyophilizingthe antiarrhythmic to form a powder for storage. The powder is thenreconstituted prior to use. This technique may be used when theantiarrhythmic is unstable in solution.

The solvent for the solution to be lyophilized may comprise water. Thesolution may be excipient-free. For instance, the solution may becryoprotectant-free.

In one or more embodiments, a suitable amount (e.g., 120 g per liter offinal solution) of drug substance may be dissolved, e.g., in about the75% of the theoretical total amount of water for injection undernitrogen bubbling. The dissolution time may be recorded and appearancemay be evaluated.

Then, the dilution to the final volume with WFI may be carried out.Final volume may be checked. Density, pH, endotoxin, bioburden, andcontent by UV may be measured both before and after sterile filtration.

The solution may be filtered before lyophilizing. For instance, a double0.22 μm filtration may be performed before filling. The filters may betested for integrity and bubble point before and after the filtration.

Pre-washed and autoclaved vials may be aseptically filled using anautomatic filling line to a target of 5 ml per vial and then partiallystoppered. In process check for fill volumes may be done by checking thefill weight every 15 minutes.

The lyophilizing is generally conducted within about 72 hours, such aswithin about 8 hours, or within about 4 hours, of the dissolving.

In one or more embodiments, the lyophilizing comprises freezing thesolution to form a frozen solution. The frozen solution is typicallyheld at an initial temperature ranging from about −40° C. to about −50°C., such as about −45° C. During the initial temperature period, thepressure around the frozen solution is typically atmospheric pressure.The initial temperature period typically ranges from about 1 hour toabout 4 hours, such about 1.5 hours to about 3 hours, or about 2 hours.

The lyophilizing may further comprise raising a temperature of thefrozen solution to a first predetermined temperature, which may rangefrom about 10° C. to about 20° C., such as about 15° C. The time for theheat ramp from the initial temperature to the first predeterminedtemperature generally ranges from about 6 hours to about 10 hours, suchas about 7 hours to about 9 hours.

During the first predetermined temperature period, the pressure aroundthe solution typically ranges from about 100 μbar to about 250 μbar,such as about 150 μbar to about 225 μbar. The solution may be held atthe first predetermined temperature for a period ranging from about 20hours to about 30 hours, such as from about 24 hours.

The lyophilizing may still further comprise raising a temperature of thesolution to a second predetermined temperature, which may range fromabout 25° C. to about 35° C., such as about 30° C. During the secondpredetermined temperature period, the pressure around the frozensolution typically ranges from about 100 μbar to about 250 μbar, such asabout 150 μbar to about 225 μbar. The solution may be held at the secondpredetermined temperature for a period ranging from about 10 hours toabout 20 hours.

In view of the above, the lyophilization cycle may comprise a freezingramp, e.g., from 20° C. to −45° C. in 65 minutes, followed by a freezesoak, e.g., at −45° C. for 2 hours. Primary drying may be accomplishedwith a heating ramp, e.g., from −45° C. to 15° C. in 8 hours, followedby a temperature hold, e.g., at 15° C. for 24 hours at a pressure of 200μbar. Secondary drying may be accomplished with a heating ramp, e.g.,from 15° C. to 30° C. in 15 minutes, followed by a temperature hold at30° C. for 15 hours at a pressure of 200 μbar. At the end of thelyophilization cycle, the vacuum may be broken with sterile nitrogen,and the vials may be automatically stoppered.

The water content of the lyophilized powder is typically less than about7 wt %, such as less than about 5 wt %, less than about 4 wt %, lessthan about 3 wt %, less than about 2 wt %, or less than about 1 wt %.

The powder is capable of being reconstituted with water at 25° C. and1.0 atmosphere and with manual agitation, in less than about 60 seconds,such as less than about 30 seconds, less than about 15 seconds, or lessthan about 10 seconds.

The powder typically has a large specific surface area that facilitatesreconstitution. The specific surface area typically ranges from about 5m²/g to about 20 m²/g, such as about 8 m²/g to 15 m²/g, or about 10 m²/gto 12 m²/g.

Upon reconstitution with water, the antiarrhythmic pharmaceutical agentsolution typically has a pH that ranges from about 2.5 to about 7, suchas about 3 to about 6.

For dry powders, the composition may be formed by spray drying,lyophilization, milling (e.g., wet milling, dry milling), and the like.

In spray drying, the preparation to be spray dried or feedstock can beany solution, coarse suspension, slurry, colloidal dispersion, or pastethat may be atomized using the selected spray drying apparatus. In thecase of insoluble agents, the feedstock may comprise a suspension asdescribed above. Alternatively, a dilute solution and/or one or moresolvents may be utilized in the feedstock. In one or more embodiments,the feed stock will comprise a colloidal system such as an emulsion,reverse emulsion microemulsion, multiple emulsion, particle dispersion,or slurry.

In one version, the antiarrhythmic pharmaceutical agent and the matrixmaterial are added to an aqueous feedstock to form a feedstock solution,suspension, or emulsion. The feedstock is then spray dried to producedried particles comprising the matrix material and the antiarrhythmicpharmaceutical agent. Suitable spray-drying processes are known in theart, for example as disclosed in WO 99/16419 and U.S. Pat. Nos.6,077,543; 6,051,256; 6,001,336; 5,985,248; and 5,976,574, which areincorporated herein by reference in their entireties.

Whatever components are selected, the first step in particle productiontypically comprises feedstock preparation. If a phospholipids-basedparticle is intended to act as a carrier for the antiarrhythmicpharmaceutical agent, the selected active agent(s) may be introducedinto a liquid, such as water, to produce a concentrated suspension. Theconcentration of antiarrhythmic pharmaceutical agent and optional activeagents typically depends on the amount of agent required in the finalpowder and the performance of the delivery device employed (e.g., thefine particle dose for a metered dose inhaler (MDI) or a dry powderinhaler (DPI)).

Any additional active agent(s) may be incorporated in a single feedstockpreparation and spray dried to provide a single pharmaceuticalcomposition species comprising a plurality of active agents. Conversely,individual active agents could be added to separate stocks and spraydried separately to provide a plurality of pharmaceutical compositionspecies with different compositions. These individual species could beadded to the suspension medium or dry powder dispensing compartment inany desired proportion and placed in the aerosol delivery system asdescribed below.

Polyvalent cation may be combined with the antiarrhythmic pharmaceuticalagent suspension, combined with the phospholipid emulsion, or combinedwith an oil-in-water emulsion formed in a separate vessel. Theantiarrhythmic pharmaceutical agent may also be dispersed directly inthe emulsion.

For example, polyvalent cation and phospholipid may be homogenized inhot distilled water (e.g., 70° C.) using a suitable high shearmechanical mixer (e.g., Ultra-Turrax model T-25 mixer) at 8000 rpm for 2to 5 min. Typically, 5 to 25 g of fluorocarbon is added dropwise to thedispersed surfactant solution while mixing. The resulting polyvalentcation-containing perfluorocarbon in water emulsion may then beprocessed using a high pressure homogenizer to reduce the particle size.Typically, the emulsion is processed for five discrete passes at 12,000to 18,000 PSI and kept at about 50° C. to about 80° C.

When the polyvalent cation is combined with an oil-in-water emulsion,the dispersion stability and dispersibility of the spray driedpharmaceutical composition can be improved by using a blowing agent, asdescribed in WO 99/16419, which is incorporated herein by reference inits entirety. This process forms an emulsion, optionally stabilized byan incorporated surfactant, typically comprising submicron droplets ofwater immiscible blowing agent dispersed in an aqueous continuous phase.The blowing agent may be a fluorinated compound (e.g., perfluorohexane,perfluorooctyl bromide, perfluorooctyl ethane, perfluorodecalin,perfluorobutyl ethane) which vaporizes during the spray-drying process,leaving behind generally hollow, porous aerodynamically light particles.Other suitable liquid blowing agents include non-fluorinated oils,chloroform, Freon® fluorocarbons, ethyl acetate, alcohols, hydrocarbons,nitrogen, and carbon dioxide gases. The blowing agent may be emulsifiedwith a phospholipid.

Although the pharmaceutical compositions may be formed using a blowingagent as described above, it will be appreciated that, in someinstances, no additional blowing agent is required and an aqueousdispersion of the antiarrhythmic pharmaceutical agent and/orpharmaceutically acceptable excipients and surfactant(s) are spray drieddirectly. In such cases, the pharmaceutical composition may possesscertain physicochemical properties (e.g., high crystallinity, elevatedmelting temperature, surface activity, etc.) that make it particularlysuitable for use in such techniques.

As needed, cosurfactants such as poloxamer 188 or span 80 may bedispersed into this annex solution. Additionally, pharmaceuticallyacceptable excipients such as sugars and starches can also be added.

The feedstock(s) may then be fed into a spray dryer. Typically, thefeedstock is sprayed into a current of warm filtered air that evaporatesthe solvent and conveys the dried product to a collector. The spent airis then exhausted with the solvent. Commercial spray dryers manufacturedby Buchi Ltd. or Niro Corp. may be modified for use to produce thepharmaceutical composition. Examples of spray drying methods and systemssuitable for making the dry powders of one or more embodiments of thepresent invention are disclosed in U.S. Pat. Nos. 6,077,543; 6,051,256;6,001,336; 5,985,248; and 5,976,574, which are incorporated herein byreference in their entireties.

Operating conditions of the spray dryer such as inlet and outlettemperature, feed rate, atomization pressure, flow rate of the dryingair, and nozzle configuration can be adjusted in order to produce therequired particle size, and production yield of the resulting dryparticles. The selection of appropriate apparatus and processingconditions are within the purview of a skilled artisan in view of theteachings herein and may be accomplished without undue experimentation.Exemplary settings are as follows: an air inlet temperature betweenabout 60° C. and about 170° C.; an air outlet between about 40° C. toabout 120° C.; a feed rate between about 3 mL/min to about 15 mL/min; anaspiration air flow of about 300 L/min; and an atomization air flow ratebetween about 25/min and about 50 L/min. The settings will, of course,vary depending on the type of equipment used. In any event, the use ofthese and similar methods allow formation of aerodynamically lightparticles with diameters appropriate for aerosol deposition into thelung.

Hollow and/or porous microstructures may be formed by spray drying, asdisclosed in WO 99/16419, which is incorporated herein by reference. Thespray-drying process can result in the formation of a pharmaceuticalcomposition comprising particles having a relatively thin porous walldefining a large internal void. The spray-drying process is also oftenadvantageous over other processes in that the particles formed are lesslikely to rupture during processing or during deagglomeration.

Pharmaceutical compositions useful in one or more embodiments of thepresent invention may alternatively be formed by lyophilization.Lyophilization is a freeze-drying process in which water is sublimedfrom the composition after it is frozen. The lyophilization process isoften used because biologics and pharmaceuticals that are relativelyunstable in an aqueous solution may be dried without exposure toelevated temperatures, and then stored in a dry state where there arefewer stability problems. With respect to one or more embodiments of theinstant invention, such techniques are particularly compatible with theincorporation of peptides, proteins, genetic material and other naturaland synthetic macromolecules in pharmaceutical compositions withoutcompromising physiological activity. Lyophilized cake containing a finefoam-like structure can be micronized using techniques known in the artto provide particles of the desired size.

The compositions of one or more embodiments of the present invention maybe administered by inhalation.

Moreover, the doses of composition that are inhaled are typically muchless than those administered by other routes and required to obtainsimilar effects, due to the efficient targeting of the inhaledcomposition to the heart.

In one or more embodiments of the invention, a pharmaceuticalcomposition comprising antiarrhythmic pharmaceutical agent isadministered to the lungs of a patient in need thereof. For example, thepatient may have been diagnosed with an arrhythmia. Examples ofarrhythmias include, but are not limited to, tachycardia,supraventricular tachycardia (SVT), paroxysmal supraventriculartachycardia (PSVT), atrial fibrillation (AF), paroxysmal atrialfibrillation (PAF), permanent atrial fibrillation, persistent atrialfibrillation, atrial flutter, paroxysmal atrial flutter, and lone atrialfibrillation.

Thus, the pharmaceutical compositions of one or more embodiments of thepresent invention can be used to treat and/or provide prophylaxis for abroad range of patients. A suitable patient for, receiving treatmentand/or prophylaxis as described herein is any mammalian patient in needthereof, preferably such mammal is a human. Examples of patientsinclude, but are not limited to, pediatric patients, adult patients, andgeriatric patients. In some embodiments, the composition is intendedonly as a treatment for rapid resolution of symptoms and is not taken asa preventative, i.e., when the patient is well, there is no need fordrug—this makes the therapy more effective and safe due to sporadic orintermittent dosing, and focused on reducing disabling symptoms.

The dosage necessary and the frequency of dosing of the antiarrhythmicpharmaceutical agent depend on the composition and concentration of theantiarrhythmic pharmaceutical agent within the composition. In somecases, the dose is less than its normal intravenous dose. The pulmonarydose is similar to intracardial doses. Inhalation avoids dilution ofdrug in the body as compared to intravenous or oral dosing.

Inhalation also avoids metabolism, such as hepatic metabolism. Forinstance, calcium channel blockers, such as diltiazem, undergosignificant hepatic metabolism when taken orally. Inhalation allowsrapid delivery of the parent diltiazem compound to the heart as a bolus.Surprisingly, administration by inhalation of diltiazem via theinhalation route according to the present invention converted atrialfibrillation to normal sinus rhythm and reduced heart rate. Thus,administration by inhalation of diltiazem is useful for treating bothatrial fibrillation and supraventricular tachycardia (SVT). In contrast,administration by IV of diltiazem is typically only used for convertingSVT to normal sinus rhythm and in atrial fibrillation to reduce heartrate (not for converting to normal sinus rhythm).

Inhalation also avoids red blood cell metabolism. For instance, thereduced dilution and short route associated with inhalation reduces redblood cell metabolism of esmolol.

Inhalation may also avoid reduced blood pressure and fainting. Forinstance, IV administration of beta blockers, such as esmolol, mayreduce mean arterial blood pressure (MAP). Inhalation allows rapiddelivery of esmolol without reducing MAP. As a result, inhalation ofbeta blockers may result in an MAP of 10 mm Hg to 20 mm Hg greater thanthe MAP resulting from IV administration of the same beta blocker.

With inhaled cardiotherapy the drug is directed to the heart from thelungs as a bolus. So, the heart sees a high concentration. The drug israpidly diluted as it passes through the heart, but the exposure time issufficient for the desired pharmacological action. Once the drug passesthrough the heart, the concentration of the drug in the overall blood isbelow the therapeutic concentration and is considered ineffective. Thetherapeutic window is the range of dosage of a drug or of itsconcentration in a bodily system that provides safe effective therapy.Anything below the minimum amount is sub-therapeutic and henceineffective in that concentration. In view of the dilution, unwantedside effects are minimized.

In one version, the antiarrhythmic may be administered daily. In thisversion, the daily dosage of antiarrhythmic pharmaceutical agent rangesfrom about 0.1 mg to about 600 mg, such as about 0.5 mg to about 500 mg,about 1 mg to about 400 mg, about 2 mg to about 300 mg, and about 3 mgto about 200 mg.

The dose may be administered during a single inhalation or may beadministered during several inhalations. The fluctuations ofantiarrhythmic pharmaceutical agent concentration can be reduced byadministering the pharmaceutical composition more often or may beincreased by administering the pharmaceutical composition less often.Therefore, the pharmaceutical composition of one or more embodiments ofthe present invention may be administered from about four times daily toabout once a month, such as about once daily to about once every twoweeks, about once every two days to about once a week, and about onceper week.

For treating a patient suffering from an arrhythmia, the amount per doseof antiarrhythmic pharmaceutical agent administered may be an amountthat is effective to treat the arrhythmia. The amount of antiarrhythmicpharmaceutical agent for the treatment of arrhythmia will generally behigher than that used for prevention, and will typically range fromabout 0.001 mg/kg to 6 mg/kg, such as from about 0.002 mg/kg to about 5mg/kg, or from about 0.005 mg/kg to about 4 mg/kg. In one exemplarytreatment regimen, the formulation in accordance with one or moreembodiments of the invention may be administered about 1 to about 4times daily, such as from about 2 to about 3 times daily. Generally, thedose of antiarrhythmic pharmaceutical agent delivered to a patient willrange from about 0.1 mg to about 600 mg, such as from about 0.2 mg to500 mg daily, depending on the condition being treated, the age andweight of the patient, and the like.

For instance, the present invention may involve a follow-up inhalationif no cardioversion occurs after an initial inhalation. Typically, if nocardioversion occurs within 30 minutes of the initial inhalation, thefollow-up dosage is higher or the same as the initial dosage.

The dosing may be guided by how the patient feels. Also oralternatively, dosing may be guided by a portable ECG. For instance, thedosing may be guided by a Holter monitor.

In another version, the pharmaceutical composition is administeredprophylactically to a patient who is likely to develop an arrhythmia.For example, a patient who has a history of arrhythmias can beprophylactically treated with a pharmaceutical composition comprisingantiarrhythmic pharmaceutical agent to reduce the likelihood ofdeveloping an arrhythmia.

The pharmaceutical composition may be administered to a patient in anyregimen which is effective to prevent an arrhythmia. Illustrativeprophylactic regimes include administering an antiarrhythmicpharmaceutical agent as described herein 1 to 21 times per week.

While not wishing to be bound by theory, by providing the antiarrhythmicpharmaceutical agent in accordance with one or more embodiments of theinvention, the systemic exposure of the antiarrhythmic pharmaceuticalagent can be reduced by avoiding initial dilution. As noted above, theantiarrhythmic pharmaceutical agent undergoes dilution as and after itpasses through the heart. Thus, the administration via inhalation ofantiarrhythmic pharmaceutical agent is believed to be safer thanintravenous delivery.

In another aspect, a method of administering comprises administering tofree breathing patients by way of an aerosol generator device and/orsystem for administration of aerosolized medicaments such as thosedisclosed in U.S. Published Application Nos. 20050235987, 20050211253,20050211245, 20040035413, and 20040011358, the disclosures of which areincorporated herein by reference in their entireties.

In one version, the pharmaceutical composition may be delivered to thelungs of a patient in the form of a dry powder. Accordingly, thepharmaceutical composition comprises a dry powder that may beeffectively delivered to the deep lungs or to another target site. Thispharmaceutical composition is in the form of a dry powder comprisingparticles having a size selected to permit penetration into the alveoliof the lungs.

In some instances, it is desirable to deliver a unit dose, such as dosesof 0.1 mg or 100 mg or greater of an antiarrhythmic pharmaceutical agentto the lung in a single inhalation. The above described phospholipidhollow and/or porous dry powder particles allow for doses of about 5 mgor greater, often greater than about 10 mg, and sometimes greater thanabout 15 mg, to be delivered in a single inhalation and in anadvantageous manner. Alternatively, a dosage may be delivered over twoor more inhalations, such as 1 to 6, 1 to 5, or 1 to 4, inhalations. Forexample, a 10 mg dosage may be delivered by providing two unit doses of5 mg each, and the two unit doses may be separately inhaled. In certainembodiments, the overall dose of the antiarrhythmic pharmaceutical agentranges from 0.1 mg to 200 mg, such as 0.5 mg to 150 mg, or 1 mg to 100mg.

The time for dosing is typically short. For nebulizers the dosing timeusually ranges from 1 minute to 20 minutes, such as from 2 minutes to 15minutes, or from 3 minutes to 10 minutes. Regarding dry powders, for asingle capsule, the total dosing time is normally less than about 1minute. Thus, the time for dosing may be less than about 5 min, such asless than about 4 min, less than about 3 min, less than about 2 min, orless than about 1 min.

In certain embodiments, the present invention is directed to a method ofself-diagnosing and treating atrial arrhythmia. The method comprisesself-diagnosing atrial arrhythmia by detecting at least one of shortnessof breath, heart palpitations, and above normal heart rate. The methodalso comprises self-administering by inhalation an effective amount ofat least one antiarrhythmic pharmaceutical agent within two hours, suchas within one hour, 30 minutes, or within 15 minutes, of theself-diagnosing.

In certain embodiments, the patient can self-titrate. For example, thepatient can self-administer, e.g., by using a nebulizer, until disablingsymptoms disappear. In some cases, the self-administering continuesuntil the patient no longer feels heart palpitations.

The time for onset of action is also typically short. For instance, thepatient may have normal sinus rhythm within 20 minutes of initiating theadministering, such as within 15 minutes, within 10 minutes, or within 5minutes of initiating the administering. The rapid onset of action isadvantageous because the longer a patient has had arrhythmia, the longerit typically takes to convert the patient to normal sinus rhythm.

In some embodiments, the method of the present invention allows thepatient to avoid other therapies, such as ablation and/or electricalcardioversion. In other embodiments, the method of the present inventionis used in combination with other therapies, such as before or afterelectrical cardioversion and/or ablation therapy.

The dispersions or powder pharmaceutical compositions may beadministered using an aerosolization device. The aerosolization devicemay be a nebulizer, a metered dose inhaler, a liquid dose instillationdevice, or a dry powder inhaler. The pharmaceutical composition may bedelivered by a nebulizer as described in WO 99/16420, by a metered doseinhaler as described in WO 99/16422, by a liquid dose instillationapparatus as described in WO 99/16421, and by a dry powder inhaler asdescribed in U.S. Published Application Nos. 20020017295 and20040105820, WO 99/16419, WO 02/83220, and U.S. Pat. No. 6,546,929,which are incorporated herein by reference in their entireties. As such,an inhaler may comprise a canister containing the particles or particlesand propellant, and wherein the inhaler comprises a metering valve incommunication with an interior of the canister. The propellant may be ahydrofluoroalkane.

The formulations of the present invention may be administered withnebulizers, such as that disclosed in PCT WO 99/16420, the disclosure ofwhich is hereby incorporated in its entirety by reference, in order toprovide an aerosolized medicament that may be administered to thepulmonary air passages of a patient in need thereof. Nebulizers areknown in the art and could easily be employed for administration of theclaimed formulations without undue experimentation. Breath activatednebulizers, as well as those comprising other types of improvementswhich have been, or will be, developed are also compatible with theformulations of the present invention and are contemplated as being within the scope thereof.

Nebulizers impart energy into a liquid pharmaceutical formulation toaerosolize the liquid, and to allow delivery to the pulmonary system,e.g., the lungs, of a patient. A nebulizer comprises a liquid deliverysystem, such as a container having a reservoir that contains a liquidpharmaceutical formulation. The liquid pharmaceutical formulationgenerally comprises an active agent that is either in solution orsuspended within a liquid medium.

In one type of nebulizer, generally referred to as a jet nebulizer,compressed gas is forced through an orifice in the container. Thecompressed gas forces liquid to be withdrawn through a nozzle, and thewithdrawn liquid mixes with the flowing gas to form aerosol droplets. Acloud of droplets is then administered to the patients respiratorytract.

In another type of nebulizer, generally referred to as a vibrating meshnebulizer, energy, such as mechanical energy, vibrates a mesh. Thisvibration of the mesh aerosolizes the liquid pharmaceutical formulationto create an aerosol cloud that is administered to the patient's lungs.

Alternatively or additionally, the pharmaceutical formulation may be ina liquid form and may be aerosolized using a nebulizer as described inWO 2004/071368, which is herein incorporated by reference in itsentirety, as well as U.S. Published application Nos. 2004/0011358 and2004/0035413, which are both herein incorporated by reference in theirentireties. Other examples of nebulizers include, but are not limitedto, the Aeroneb®Go or Aeroneb®Pro nebulizers, available from AerogenLtd. of Galway, Ireland; the PARI eFlow and other PARI nebulizersavailable from PARI Respiratory Equipment, Inc. of Midlothian, Va.; theLumiscope® Nebulizer 6600 or 6610 available from Lumiscope Company, Inc.of East Brunswick, N.J.; and the Omron NE-U22 available from OmronHealthcare, Inc. of Kyoto, Japan.

It has been found that a nebulizer of the vibrating mesh type, such asone that that forms droplets without the use of compressed gas, such asthe Aeroneb® Pro provides unexpected improvement in dosing efficiencyand consistency. By generating fine droplets by using a vibratingperforated or unperforated membrane, rather than by introducingcompressed air, the aerosolized pharmaceutical formulation can beintroduced without substantially affecting the flow characteristics. Inaddition, the generated droplets when using a nebulizer of this type areintroduced at a low velocity, thereby decreasing the likelihood of thedroplets being driven to an undesired region.

In still another type of nebulizer, ultrasonic waves are generated todirectly vibrate and aerosolize the pharmaceutical formulation.

As noted above, the present invention may also involve a dry powderinhaler. A specific version of a dry powder aerosolization apparatus isdescribed in U.S. Pat. Nos. 4,069,819 and 4,995,385, which areincorporated herein by reference in their entireties. Another usefuldevice, which has a chamber that is sized and shaped to receive acapsule so that the capsule is orthogonal to the inhalation direction,is described in U.S. Pat. No. 3,991,761, which is incorporated herein byreference in its entirety. As also described in U.S. Pat. No. 3,991,761,a puncturing mechanism may puncture both ends of the capsule. In anotherversion, a chamber may receive a capsule in a manner where air flowsthrough the capsule as described for example in U.S. Pat. Nos. 4,338,931and 5,619,985, which are incorporated herein by reference in theirentireties. In another version, the aerosolization of the pharmaceuticalcomposition may be accomplished by pressurized gas flowing through theinlets, as described for example in U.S. Pat. Nos. 5,458,135; 5,785,049;and 6,257,233, or propellant, as described in WO 00/72904 and U.S. Pat.No. 4,114,615, which are incorporated herein by reference. These typesof dry powder inhalers are generally referred to as active dry powderinhalers.

Other dry powder inhalers include those available from BoehringerIngelheim (e.g., Respimat inhaler), Hovione (e.g., FlowCaps inhaler),Plastiape (e.g., Osmohaler inhaler), and MicroDose. The presentinvention may also utilize condensation aerosol devices, available fromAlexza, Mountain View, Calif. Yet another useful inhaler is disclosed inWO 2008/051621, which is incorporated herein by reference in itsentirety.

The pharmaceutical formulations disclosed herein may also beadministered to the lungs of a patient via aerosolization, such as witha metered dose inhaler. The use of such formulations provides forsuperior dose reproducibility and improved lung deposition as disclosedin WO 99/16422, hereby incorporated in its entirety by reference. MDIsare known in the art and could easily be employed for administration ofthe claimed dispersions without undue experimentation. Breath activatedMDIs and pressurized MDIs (pMDIs), as well as those comprising othertypes of improvements which have been, or will be, developed are alsocompatible with the formulations of the present invention and, as such,are contemplated as being within the scope thereof.

Along with DPIs, MDIs and nebulizers, it will be appreciated that theformulations of one or more embodiments of the present invention may beused in conjunction with liquid dose instillation or LDI techniques asdisclosed in, for example, WO 99/16421, which is incorporated herein byreference in its entirety. Liquid dose instillation involves the directadministration of a formulation to the lung. With respect to LDI theformulations are preferably used in conjunction with partial liquidventilation or total liquid ventilation. Moreover, one or moreembodiments of the present invention may further comprise introducing atherapeutically beneficial amount of a physiologically acceptable gas(such as nitric oxide or oxygen) into the pharmaceutical microdispersionprior to, during or following administration.

The pharmaceutical composition of one or more embodiments of the presentinvention typically has improved emitted dose efficiency. Accordingly,high doses of the pharmaceutical composition may be delivered using avariety of aerosolization devices and techniques.

The emitted dose (ED) of the particles of the present invention may begreater than about 30%, such as greater than about 40%, greater thanabout 50%, greater than about 60%, or greater than about 70%.

One or more embodiments are directed to kits. For instance, the kit mayinclude an aerosolization device and a container, e.g., unit dosereceptacle, containing aerosolizable antiarrhythmic pharmaceuticalagent, e.g., liquid or dry powder.

The kit may further comprise a package, such as a bag, that contains theaerosolization device and the container.

In view of the above, the present invention involves methods to treatacute episodes of and/or chronic arrhythmias. In certain embodiments,the treating comprises acute treatment after detection of atrialarrhythmia.

This method of treatment results in a pulsatile pharmacokinetic profileand transient pharmacodynamic effect mimicking the effect of an IV. Thismethod delivers high drug concentrations that are safe and effective tothe heart, while the distribution to the rest of the body results in thedrug being diluted to sub-therapeutic levels. This method is theshortest route of delivery to the heart next to intra-cardial injection.This provides the convenience of self-administration like the“pill-in-the-pocket” approach, but the effectiveness and fast onset ofaction of an IV. Although the delivery of medications through the lungfor systemic effect is not new, it was thought it wouldn't be effectiveto the heart, because of the fast passage of drug through it. The PK/PDmodeling originating this invention shows that the drug exposure issufficient for therapeutic effect at a much lower dose compared to otherroutes of administration. This method ensures dug concentrations inoverall plasma are much lower than what is achieved by oral/IV henceminimizing drug-drug interactions and side effects.

The present invention will be further illustrated by way of thefollowing Examples. These examples are non-limiting and do not restrictthe scope of the invention. Unless stated otherwise, all percentages,parts, etc. presented in the examples are by weight.

EXAMPLES Example 1 Prophetic Analytical Model Involving Verapamil andLidocaine

Published pharmacokinetic and pharmacodynamic models (FIG. 4) showrelationships between drug concentration in coronary blood and desiredcoronary effect. IV drug information was used from published literature.HARRISON et al., “Effect of Single Doses of Inhaled Lignocaine on FEV1and Bronchial Reactivity in Asthma,” Respir Med., 12:1359-635 (December1992). Inhaled drug information was simulated based on known propertiesof pulmonary small molecule absorption.

FIG. 5 shows the different time concentration profiles of drugadministered via the IV and inhalation routes. Verapamil was selected asan example heart drug as it possesses both cardiac rate and rhythmcontrol properties and is often used to rescue acute arrhythmia episodes(e.g.: paroxysmal ventricular tachycardia and paroxysmal atrialfibrillation).

FIG. 6 also shows different time concentration profiles of drugadministered via the IV and inhalation routes. Lidocaine was selected asan example heart drug. This PK/PD modeling with lidocaine shows samehigh feasibility.

Example 2 Effects of Intratracheal (IT) Administration ofAnti-Arrhythmic Compounds on the Ventricular Response of Dogs withInduced Atrial Fibrillation and Supraventricular Tachycardia (SVT)

Objective:

To evaluate the effects/efficacy of common antiarrhythmic drugs whengiven via the pulmonary route, on the electrophysiological response ofanesthetized dogs with induced atrial fibrillation and supraventriculartachycardia.

Animal Models Used

Atrial Fibrillation Model:

Anesthesia/Surgical Preparation:

A venous catheter was placed in a peripheral vessel (i.e., cephalic) foradministration of anesthetic. For anesthesia induction, all animals weregiven morphine sulfate (˜2 mg/kg) and a bolus of alpha chloralose (˜100mg/kg) intravenously through the venous catheter. Anesthesia wassustained with alpha chloralose (35-75 mg/kg/hour IV), until completionof the study (<2 hours). Following induction, animals wereendotracheally intubated and mechanically ventilated (˜12 breaths/minutewith a tidal volume of 200-300 mL). Subsequently, a cut-down on ajugular vein permitted introduction of a pacing lead into the rightatrium. Transthoracic electrodes forming ECG lead II were placed. Fortest/vehicle article delivery, a 4F catheter was introduced through thetrachea and wedged into a small airway, and a venous catheter was placedin a peripheral vessel (i.e., cephalic).

Experiments:

Following instrumentation and hemodynamic stabilization (for at least 15minutes), phenylephrine was continuously infused (2 ug/kg/min IV) toelevate the systemic arterial pressure and increase vagal(parasympathetic) efferent activity for the duration of the study.Approximately 5 min after administration of this parasympathomimetic wasstarted; the following experiments were performed:

First, the right atrium was paced (20 V, 40 Hz, 4 ms pulse) for 15minutes, and following pacing discontinuation, atrial fibrillationensued. Approximately 3 minutes after pacing was stopped and atrialfibrillation was observed, the animals were given vehicle (˜3 mL)intra-tracheally (IT); the duration between dosing and, (if observed)the return to sinus rhythm and/or the ventricular rate was noted.Observations were made for up to 10 minutes.

Subsequently, atrial fibrillation was re-established via 15-minutepacing cycle(s), as described above. Once pacing was discontinued andatrial fibrillation was observed/stable for 3 minutes, the animals wereadministered the vehicle or one of the test articles, delivered as abolus (˜3 mL) directly into a small airway through the intratrachealcatheter. Vehicle was only water. In the case of flecainide as the testarticle, the concentration was 15 mg of flecainide/3 ml of water.Following dosing, the duration between cessation of administration and,if observed, return to sinus rhythm and/or ventricular rate were noted;observations were made for up to 10 minutes. Overall, threegroups/test-articles were studied, and up to two animals were assignedto each group (n=2/group): one group received flecainide acetate (2-4mg/kg, FLE), while the others received diltiazem (0.25-0.50 mg/kg, DIL)or dofetilide (20-60 ug/kg, DOF); only one test article was administeredper animal. The experimental protocol(s) are summarized in FIG. 7.

Supraventricular Tachycardia Model:

Anesthesia/Surgical Preparation:

A venous catheter was placed in a peripheral vessel (i.e., cephalic) foradministration of anesthetic(s). For anesthesia induction, all animalswere given a combination of diazepam (˜0.5 mg/kg) and ketamine (˜10mg/kg) intravenously through this venous catheter. Anesthesia wassustained until completion of the study with an intravenous infusion ofpentobarbital (5-15 mg/kg/hr). Following induction, animals wereendotracheally intubated and mechanically ventilated (˜12 breaths/minwith a tidal volume of 200-300 mL).

Subsequently, a cut-down on a jugular vein permitted the introduction ofa pacing lead into the right atrium. Similarly, for arterial pressuremonitoring, a solid-state micromanometer catheter (Millar Instruments)was advanced into the aortic root via a cut-down over an artery (e.g.,femoral, carotid). Transthoracic electrodes forming ECG lead II wasplaced. For vehicle/test article delivery, a 4F catheter was introducedthrough the trachea and wedged into a small airway, and a venouscatheter was placed in a peripheral vessel (i.e., cephalic).

Experiments:

Following instrumentation/hemodynamic stabilization (for at least 15minutes), right atrial pacing (5-10 V, 40 Hz, 2 ms pulses) wasestablished in order to induce supraventricular tachycardia (SVT);pacing and SVT was sustained throughout the duration of the experiments.Approximately 5 minutes after onset of SVT and while monitoringECG/arterial pressure continuously, the animals were administered threeescalating doses (one at a time) of a test article; each dose wasdelivered as a bolus (˜3 mL) directly into a small airway through theintratracheal catheter (IT). Following dosing, the heart-rate (HR) andarterial pressure response were monitored for 15 minutes.

Subsequently (once the response to three IT doses had been recorded),hemodynamic recovery was allowed for approximately 30 minutes, and theelectrocardiographic/hemodynamic response to the highest test-articledose was re-evaluated; however, for comparison purposes, this dose wasdelivered intravenously (IV).

Overall, two groups/test-articles were studied, and up to two animalswere assigned to each group (n=2/group): one group received esmolol HCL(0.5-1.0 mg/kg, ESM), while the other received adenosine (0.25-1.0mg/kg, ADN); only one test article was administered to per animal. Theexperimental protocol(s) are summarized in FIG. 8.

Observations:

Atrial Fibrillation:

Among the three test articles (flecainide, diltiazem and dofetilide)studied, both flecainide and diltiazem rapidly converted the AtrialFibrillation to normal sinus rhythm, while dofetilide marginally slowedthe ventricular rate.

Vehicle:

FIG. 9 shows the dog in atrial fibrillation prior to administration ofeither vehicle or test article. FIG. 10 shows an example of the vehiclehaving no effect on the arrhythmia. Vehicle administered in same volumesas the test articles had no effect on the arrhythmia.

Flecainide:

At pulmonary dose between 2-4 mg/kg body weight, flecainide convertedthe induced atrial fibrillation to normal sinus rhythm. Large doses ofthe drug also resulted in slower ventricular rates. None to minimal dropin mean arterial pressure was noted. Neither dogs exhibited any knownadverse events such as proarrhythmia. See FIGS. 11 and 12.

Diltiazem:

At pulmonary doses of 0.25 mg/kg body weight, diltiazem converted theinduced atrial fibrillation to normal sinus rhythm and also prolongedthe PQ. Heart rate also slowed down marginally. There was however anotable drop in mean arterial blood pressure (MAP). See FIG. 13.

Dofetilide:

At escalating pulmonary doses of 10-40 mcg/kg body weight, dofetilidecaused minor reduction in heart rate.

Supraventricular Tachycardia (SVT):

Diltiazem:

The diltiazem delivered via the pulmonary and IV routes were comparablein all aspects. The Mean Arterial Pressure (MAP) dropped significantlyin both cases, attributed directly to the dose of the drug. Diltiazemalso prolonged the PR interval indicating that the drug delivered byeither IV or pulmonary routes has the ability to correct the SVT tonormal sinus rhythm. The timing of the electrophysiological change wascomparable between IV and pulmonary. See FIGS. 14 and 15.

Esmolol:

Elevating doses of esmolol were shown to produce 2^(nd) degree AV blockat lower doses and also affecting the PR intervals in the ECG traces.See FIGS. 16-20.

However, higher doses of esmolol at 1.0 mg/kg did not produce the sameelectrophysiological effects. It is noteworthy that esmolol deliveredvia the lung did not cause a drop in MAP in any of the doses.

Adenosine:

Adenosine administered via the lung did not have any effect on theheart. Adenosine is known to metabolize differently in different speciesand it is not clear whether the effect was due to localized adenosineadministration or the model not being sensitive enough.

Summary

There was a clear cardiovascular effect of diltiazem, flecainide, and aprobable effect of esmolol and dofetilide when given intratracheally.These drugs comprise four divergent classes of chemical andpharmacological agents. Although a clear response was not observed withadenosine, it is still considered worthy of evaluation in more specificanimal models. The responses mimicked qualtitatively those of the IVroute and known physiological effects of all test articles fordiltiazem, flecainide, and esmolol. There may be some physical orphysicochemical property of adenosine that precludes absorption from thetracheal route in this animal model. Additionally, administration into asingle small airway would not be expected to produce the same exposureas administration by inhalation where the surface for diffusion would bemany orders of magnitude greater.

These studies confirm the physiological effects of divergent chemicalson cardiovascular function. The intratracheal route of administrationpossesses 3 potential advantages. (1) It is the shortest route frompoint of administration to the target organ—the heart. (2) There is lessdilution therefore a higher concentration to the target organ would beexpected. (3) There would be a reduction in metabolism (i.e., first passeffect) since there is no organ (e.g., liver) for metabolizing betweensite of administration and target organ.

Example 3 Preliminary Evaluation of Solubility and Taste ofAntiarrhythmic Pharmaceutical Agents when Administered as an Aerosol

Objective:

To evaluate the solubilities of flecainide acetate and diltiazemhydrochloride in water and to evaluate the acceptability of taste andaftertaste of these two drugs for administration as liquid aerosols.

Experiment and Observations Preformulation Studies

Diltiazem's solubility was >90 mg/mL at room temperature. The pH of a3.5 mg/mL solution of diltiazem in water was 6.7. At 50 mg/mL, adiltiazem in water solution was about 80% to isotonic.

Flecainide's solubility was about 30 mg/mL at room temperature. The pHof a 2.6 mg/mL solution of flecainide in water was 5.0. At 30 mg/mL, aflecainide in water solution was about 50% to isotonic.

The following solution strengths were prepared for taste evaluation: (1)diltiazem hydrochloride—50 mg/ml solution in distilled water; and (2)flecainide acetate—30 mg/ml solution in distilled water. The solutionswere clear with no visible particulate matter.

Inhalation Device:

The Aeroneb®GO device was used because it is a simple-to-use devicedeveloped specifically for patients who require respiratory therapy inand away from the home. The device can be used by patients of all ages(infant through adult) and aerosolizes solutions intended forinhalation. Aeroneb® Go works with either an AC wall controller or abattery pack, and can be cleaned with soap and water. More details aboutthis device can be obtained at www.aerogen.com.

Inhalation Procedure:

Volunteers:

Number of subjects: 2 healthy male volunteers

Volunteer-1: age—48

Volunteer-2: age—63

Nebulizer Testing:

Water was poured into the nebulizer cup, and the nebulizer was turnedon. The visible cloud of aerosol generated when the nebulizer was turnedon was treated as a qualitative aerosol standard.

Flecainide Acetate:

About 1 ml of the 30 mg/ml solution was poured into the cup of thenebulizer. The nebulizer was turned on and the resulting aerosol wassimilar to but not as dense as the aerosol formed with the water alone.

The nebulizer was then placed in the mouth and switched on. Deep lunginhalation was performed through the nebulizer. About 40 μl (˜1.2 mg offlecainide acetate) of the test solution was inhaled. The inhaled dosewas sub-therapeutic in nature as it was much less than the regular 100mg administered as tablets. Flecainide acetate is also available as anIV injection in Europe as 10 mg/ml strength in 15 ml ampoules.

Diltiazem Hydrochloride:

About 1 ml of the 50 mg/ml solution was poured into the cup of thenebulizer. The nebulizer was turned on and the resulting aerosol wassimilar to but not as dense as the aerosol formed with the water alone.

The nebulizer was then placed in the mouth and a switched on. Deep lunginhalation was performed through the nebulizer. About 40 μl (˜2 mg ofdiltiazem hydrochloride) of the test solution was inhaled. The inhaleddose was sub-therapeutic in nature as it was much less than the IVinjection marketed in the U.S. as 5 mg/ml in 5 ml vials.

CONCLUSIONS AND OBSERVATIONS

-   -   1. The visible aerosol characteristics test solutions were        similar to each other but not as dense as the water.    -   2. Flecainide acetate: The taste feedback from both volunteers        was very similar.        -   a. Taste: Mildly bitter taste felt in the back of the tongue        -   b. Aftertaste: There was none to little aftertaste 5 minutes            after the inhalation maneuver.    -   3. Diltiazem hydrochloride: Water was inhaled to wash out any of        the flecainide residues. The taste feedback from both volunteers        was very similar.        -   a. Taste: Mildly bitter taste felt in the back of the tongue        -   b. Aftertaste: There was none to little aftertaste 5 minutes            after the inhalation maneuver.    -   4. Other observations:        -   a. No burning sensations was felt in the mouth, throat, or            lungs        -   b. No visible adverse events were observed. Both volunteers            rested for 60 minutes after dosing.

The foregoing embodiments and advantages are merely exemplary and arenot to be construed as limiting the present invention. The descriptionof the present invention is intended to be illustrative, and not tolimit the scope of the claims. Many alternatives, modifications, andvariations will be apparent to those skilled in the art.

Having now fully described this invention, it will be understood tothose of ordinary skill in the art that the methods of the presentinvention can be carried out with a wide and equivalent range ofconditions, formulations, and other parameters without departing fromthe scope of the invention or any embodiments thereof.

All patents and publications cited herein are hereby fully incorporatedby reference in their entirety. The citation of any publication is forits disclosure prior to the filing date and should not be construed asan admission that such publication is prior art or that the presentinvention is not entitled to antedate such publication by virtue ofprior invention.

1-178. (canceled)
 179. A method of treating atrial arrhythmia,comprising: administering to a pulmonary vein through a pulmonary tractand through use of an aerosolization device an effective amount of atleast one antiarrhythmic pharmaceutical agent selected from a groupconsisting of class I, class II, class III, and class IVantiarrhythmics, to a patient in need thereof, wherein the effectiveamount of the at least one antiarrhythmic pharmaceutical agent is atotal amount from 0.1 mg to 200 mg administered over multipleinhalations, wherein the at least one antiarrhythmic pharmaceuticalagent level peaks in a coronary sinus of the heart at a time between 30seconds and 20 minutes from initiation of the pulmonary administration,and wherein the patient's sinus rhythm is restored to normal within 30minutes of initiating the administration.
 180. The method of claim 179,wherein the concentration of the at least one antiarrhythmicpharmaceutical agent in the coronary sinus of the heart ranges between0.1 mg/L and 60 mg/L at 2.5 minutes after initiation of pulmonaryadministration, and the concentration of the at least one antiarrhythmicpharmaceutical agent in the coronary sinus of the heart is less than 0.1mg/L at 30 minutes after initiation of pulmonary administration, orwherein 10% to 60% of a nominal dose of the administered at least oneantiarrhythmic pharmaceutical agent reaches the coronary sinus.
 181. Themethod of claim 179, wherein the concentration of the at least oneantiarrhythmic pharmaceutical agent in the coronary sinus of the heartis between 0.1 mg/L and 20 mg/L at 2.5 minutes after initiation ofpulmonary administration, and the concentration of the at least oneantiarrhythmic pharmaceutical agent in the coronary sinus of the heartis less than 0.1 mg/L at 30 minutes after initiation of pulmonaryadministration, or wherein between 5% and 60% of a nominal dose of theadministered at least one antiarrhythmic pharmaceutical agent reachesthe coronary sinus.
 182. The method of claim 179, comprising pulmonaryadministration of the at least one antiarrhythmic in up to 6inhalations.
 183. The method of claim 179, wherein the atrial arrhythmiacomprises tachycardia.
 184. The method of claim 183, wherein thetachycardia comprises supraventricular tachycardia, paroxysmalsupraventricular tachycardia, atrial fibrillation, paroxysmal atrialfibrillation, acute episodes in persistent and permanent atrialfibrillation, atrial flutter, paroxysmal atrial flutter or lone atrialfibrillation.
 185. The method of claim 179, comprising administering aliquid, dry powder, or nebulized droplets comprising the at least oneantiarrhythmic pharmaceutical agent, wherein the powder or nebulizeddroplets have a mass median aerodynamic diameter of less than 10 μm.186. The method of claim 179, wherein the antiarrhythmic pharmaceuticalagent is a class I antiarrhythmic.
 187. The method of claim 186, whereinthe class I antiarrhythmic is a class Ia, Ib, or Ic antiarrhythmic. 188.The method of claim 179, wherein the antiarrhythmic pharmaceutical agentis a class II antiarrhythmic.
 189. The method of claim 188, wherein theclass II antiarrhythmic is esmolol HCl.
 190. The method of claim 189,wherein dosage of the esmolol HCl is between 0.5 and 0.75 mg/kg bodyweight.
 191. The method of claim 179, wherein the antiarrhythmicpharmaceutical agent is a class IV antiarrhythmic.
 192. The method ofclaim 191, wherein the class IV antiarrhythmic is diltiazem.
 193. Themethod of claim 192, wherein dosage of the diltiazem is 0.25 mg/kg bodyweight.
 194. The method of claim 179, wherein the at least oneantiarrhythmic pharmaceutical agent level peaks in the coronary sinus ofthe heart at a time between 1 minute and 10 minutes.
 195. The method ofclaim 179, wherein the aerosolization device is a nebulizer configuredto administer the at least one antiarrhythmic pharmaceutical agent in aliquid pharmaceutical formulation, wherein the aerosolization occurs atroom temperature.
 196. The method of claim 179, wherein the at least oneantiarrhythmic pharmaceutical agent is self-administered by the patient.197. A method of treating atrial arrhythmia, comprising: administeringto a pulmonary vein through a pulmonary tract and through use of anaerosolization device an effective amount of at least one antiarrhythmicpharmaceutical agent selected from a group consisting of class I, classII, class III, and class IV antiarrhythmics, to a patient in needthereof, wherein the patient self-administers and self-titrates aneffective inhaled dose of at least one antiarrhythmic pharmaceuticalagent for a conversion of atrial arrhythmia to normal sinus rhythm,wherein the at least one antiarrhythmic pharmaceutical agent level peaksin a coronary sinus of the heart at a time between 30 seconds and 20minutes from initiation of the pulmonary administration, and wherein thepatient's sinus rhythm is restored to normal within 30 minutes ofinitiating the administration.
 198. The method of claim 197, wherein theconcentration of the at least one antiarrhythmic pharmaceutical agent inthe coronary sinus of the heart ranges between 0.1 mg/L and 60 mg/L at2.5 minutes after initiation of pulmonary administration, and theconcentration of the at least one antiarrhythmic pharmaceutical agent inthe coronary sinus of the heart is less than 0.1 mg/L at 30 minutesafter initiation of pulmonary administration, or wherein 10% to 60% ofthe nominal dose of the administered at least one antiarrhythmicpharmaceutical agent reaches the coronary sinus.
 199. The method ofclaim 197, wherein the concentration of the at least one antiarrhythmicpharmaceutical agent in the coronary sinus of the heart is between 0.1mg/L and 20 mg/L at 2.5 minutes after initiation of pulmonaryadministration, and the concentration of the at least one antiarrhythmicpharmaceutical agent in the coronary sinus of the heart is less than 0.1mg/L at 30 minutes after initiation of pulmonary administration, orwherein between 5% and 60% of the nominal dose of the administered atleast one antiarrhythmic pharmaceutical agent reaches the coronarysinus.
 200. The method of claim 197, comprising pulmonary administrationof the at least one antiarrhythmic in up to 6 inhalations.
 201. Themethod of claim 197, wherein the atrial arrhythmia comprisestachycardia.
 202. The method of claim 201, wherein the tachycardiacomprises supraventricular tachycardia, paroxysmal supraventriculartachycardia, atrial fibrillation, paroxysmal atrial fibrillation, acuteepisodes in persistent and permanent atrial fibrillation, atrialflutter, paroxysmal atrial flutter or lone atrial fibrillation.
 203. Themethod of claim 197, comprising administering a liquid, dry powder, ornebulized droplets comprising the at least one antiarrhythmicpharmaceutical agent, wherein the dry powder or nebulized droplets havea mass median aerodynamic diameter of less than 10 μm.
 204. The methodof claim 197, wherein the antiarrhythmic pharmaceutical agent is a classI antiarrhythmic.
 205. The method of claim 204, wherein the class Iantiarrhythmic is a class Ia, Ib, or Ic antiarrhythmic.
 206. The methodof claim 197, wherein the antiarrhythmic pharmaceutical agent is a classII antiarrhythmic.
 207. The method of claim 206, wherein the class IIantiarrhythmic is esmolol HCl.
 208. The method of claim 207, wherein theeffective inhaled dose of the esmolol HCl is between 0.5 and 0.75 mg/kgbody weight.
 209. The method of claim 197, wherein the antiarrhythmicpharmaceutical agent is a class IV antiarrhythmic.
 210. The method ofclaim 209, wherein the class IV antiarrhythmic is diltiazem.
 211. Themethod of claim 210, wherein the effective inhaled dose of the diltiazemis 0.25 mg/kg body weight.
 212. The method of claim 197, wherein the atleast one antiarrhythmic pharmaceutical agent level peaks in thecoronary sinus of the heart at a time between 1 minute and 10 minutes.213. The method of claim 197, wherein the aerosolization device is anebulizer configured to administer the at least one antiarrhythmicpharmaceutical agent in a liquid pharmaceutical formulation, wherein theaerosolization occurs at room temperature.